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overflow: hidden; text-overflow: ellipsis; -webkit-line-clamp: 3; -webkit-box-orient: vertical; }</style><div class="col-xs-12 clearfix"><div class="u-floatLeft"><h1 class="PageHeader-title u-m0x u-fs30">Allosteric regulation</h1><div class="u-tcGrayDark">24 Followers</div><div class="u-tcGrayDark u-mt2x">Recent papers in <b>Allosteric regulation</b></div></div></div></div></div></div><div class="TabbedNavigation"><div class="container"><div class="row"><div class="col-xs-12 clearfix"><ul class="nav u-m0x u-p0x list-inline u-displayFlex"><li class="active"><a href="https://www.academia.edu/Documents/in/Allosteric_regulation">Top Papers</a></li><li><a href="https://www.academia.edu/Documents/in/Allosteric_regulation/MostCited">Most Cited Papers</a></li><li><a href="https://www.academia.edu/Documents/in/Allosteric_regulation/MostDownloaded">Most Downloaded Papers</a></li><li><a href="https://www.academia.edu/Documents/in/Allosteric_regulation/MostRecent">Newest Papers</a></li><li><a class="" href="https://www.academia.edu/People/Allosteric_regulation">People</a></li></ul></div><style type="text/css">ul.nav{flex-direction:row}@media(max-width: 567px){ul.nav{flex-direction:column}.TabbedNavigation li{max-width:100%}.TabbedNavigation li.active{background-color:var(--background-grey, #dddde2)}.TabbedNavigation li.active:before,.TabbedNavigation li.active:after{display:none}}</style></div></div></div><div class="container"><div class="row"><div class="col-xs-12"><div class="u-displayFlex"><div class="u-flexGrow1"><div class="works"><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_22476080" data-work_id="22476080" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/22476080/Metabotropic_Glutamate_Receptors_Physiology_Pharmacology_and_Disease">Metabotropic Glutamate Receptors: Physiology, Pharmacology, and Disease</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">The metabotropic glutamate receptors (mGluRs) are family C G-protein-coupled receptors that participate in the modulation of synaptic transmission and neuronal excitability throughout the central nervous system. The mGluRs bind glutamate... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_22476080" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">The metabotropic glutamate receptors (mGluRs) are family C G-protein-coupled receptors that participate in the modulation of synaptic transmission and neuronal excitability throughout the central nervous system. The mGluRs bind glutamate within a large extracellular domain and transmit signals through the receptor protein to intracellular signaling partners. A great deal of progress has been made in determining the mechanisms by which mGluRs are activated, proteins with which they interact, and orthosteric and allosteric ligands that can modulate receptor activity. The widespread expression of mGluRs makes these receptors particularly attractive drug targets, and recent studies continue to validate the therapeutic utility of mGluR ligands in neurological and psychiatric disorders such as Alzheimer's disease, Parkinson's disease, anxiety, depression, and schizophrenia.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/22476080" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="fc2fc5089c6718d93fc4c536196bd280" rel="nofollow" data-download="{"attachment_id":43097691,"asset_id":22476080,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/43097691/download_file?st=MTc0MDE1NDMyOCw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="43982549" href="https://independent.academia.edu/ConnJeffrey">Jeffrey Conn</a><script data-card-contents-for-user="43982549" type="text/json">{"id":43982549,"first_name":"Jeffrey","last_name":"Conn","domain_name":"independent","page_name":"ConnJeffrey","display_name":"Jeffrey Conn","profile_url":"https://independent.academia.edu/ConnJeffrey?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_22476080 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="22476080"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 22476080, container: ".js-paper-rank-work_22476080", }); 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$(".js-view-count[data-work-id=22476080]").text(description); $(".js-view-count-work_22476080").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_22476080").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="22476080"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">7</a>  </div><span class="InlineList-item-text u-textTruncate u-pl9x"><a class="InlineList-item-text" data-has-card-for-ri="140" rel="nofollow" href="https://www.academia.edu/Documents/in/Pharmacology">Pharmacology</a>, <script data-card-contents-for-ri="140" type="text/json">{"id":140,"name":"Pharmacology","url":"https://www.academia.edu/Documents/in/Pharmacology?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="38831" rel="nofollow" href="https://www.academia.edu/Documents/in/Signal_Transduction">Signal Transduction</a>, <script data-card-contents-for-ri="38831" type="text/json">{"id":38831,"name":"Signal Transduction","url":"https://www.academia.edu/Documents/in/Signal_Transduction?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="47884" rel="nofollow" href="https://www.academia.edu/Documents/in/Biological_Sciences">Biological Sciences</a>, <script data-card-contents-for-ri="47884" type="text/json">{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="133186" rel="nofollow" href="https://www.academia.edu/Documents/in/Pharmacology_and_toxicology">Pharmacology and toxicology</a><script data-card-contents-for-ri="133186" type="text/json">{"id":133186,"name":"Pharmacology and toxicology","url":"https://www.academia.edu/Documents/in/Pharmacology_and_toxicology?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=22476080]'), work: {"id":22476080,"title":"Metabotropic Glutamate Receptors: Physiology, Pharmacology, and Disease","created_at":"2016-02-26T06:13:49.139-08:00","url":"https://www.academia.edu/22476080/Metabotropic_Glutamate_Receptors_Physiology_Pharmacology_and_Disease?f_ri=1970697","dom_id":"work_22476080","summary":"The metabotropic glutamate receptors (mGluRs) are family C G-protein-coupled receptors that participate in the modulation of synaptic transmission and neuronal excitability throughout the central nervous system. The mGluRs bind glutamate within a large extracellular domain and transmit signals through the receptor protein to intracellular signaling partners. A great deal of progress has been made in determining the mechanisms by which mGluRs are activated, proteins with which they interact, and orthosteric and allosteric ligands that can modulate receptor activity. The widespread expression of mGluRs makes these receptors particularly attractive drug targets, and recent studies continue to validate the therapeutic utility of mGluR ligands in neurological and psychiatric disorders such as Alzheimer's disease, Parkinson's disease, anxiety, depression, and schizophrenia.","downloadable_attachments":[{"id":43097691,"asset_id":22476080,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":43982549,"first_name":"Jeffrey","last_name":"Conn","domain_name":"independent","page_name":"ConnJeffrey","display_name":"Jeffrey Conn","profile_url":"https://independent.academia.edu/ConnJeffrey?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":140,"name":"Pharmacology","url":"https://www.academia.edu/Documents/in/Pharmacology?f_ri=1970697","nofollow":true},{"id":38831,"name":"Signal Transduction","url":"https://www.academia.edu/Documents/in/Signal_Transduction?f_ri=1970697","nofollow":true},{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true},{"id":133186,"name":"Pharmacology and toxicology","url":"https://www.academia.edu/Documents/in/Pharmacology_and_toxicology?f_ri=1970697","nofollow":true},{"id":139002,"name":"Alternative splicing","url":"https://www.academia.edu/Documents/in/Alternative_splicing?f_ri=1970697"},{"id":635694,"name":"Alternative Splicing","url":"https://www.academia.edu/Documents/in/Alternative_Splicing-1?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_19453649" data-work_id="19453649" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/19453649/Crystal_structure_of_IgE_bound_to_its_B_cell_receptor_CD23_reveals_a_mechanism_of_reciprocal_allosteric_inhibition_with_high_affinity_receptor_Fc_RI">Crystal structure of IgE bound to its B-cell receptor CD23 reveals a mechanism of reciprocal allosteric inhibition with high affinity receptor Fc RI</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">The role of IgE in allergic disease mechanisms is performed principally through its interactions with two receptors, FcεRI on mast cells and basophils, and CD23 (FcεRII) on B cells. The former mediates allergic hypersensitivity, the... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_19453649" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">The role of IgE in allergic disease mechanisms is performed principally through its interactions with two receptors, FcεRI on mast cells and basophils, and CD23 (FcεRII) on B cells. The former mediates allergic hypersensitivity, the latter regulates IgE levels, and both receptors, also expressed on antigen-presenting cells, contribute to allergen uptake and presentation to the immune system. We have solved the crystal structure of the soluble lectin-like &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;head&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; domain of CD23 (derCD23) bound to a subfragment of IgE-Fc consisting of the dimer of Cε3 and Cε4 domains (Fcε3-4). One CD23 head binds to each heavy chain at the interface between the two domains, explaining the known 2:1 stoichiometry and suggesting mechanisms for cross-linking membrane-bound trimeric CD23 by IgE, or membrane IgE by soluble trimeric forms of CD23, both of which may contribute to the regulation of IgE synthesis by B cells. The two symmetrically located binding sites are distant from the single FcεRI binding site, which lies at the opposite ends of the Cε3 domains. Structural comparisons with both free IgE-Fc and its FcεRI complex reveal not only that the conformational changes in IgE-Fc required for CD23 binding are incompatible with FcεRI binding, but also that the converse is true. The two binding sites are allosterically linked. We demonstrate experimentally the reciprocal inhibition of CD23 and FcεRI binding in solution and suggest that the mutual exclusion of receptor binding allows IgE to function independently through its two receptors.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/19453649" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="f7ef08764675e1de53837e3ca35b8e98" rel="nofollow" data-download="{"attachment_id":42090309,"asset_id":19453649,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/42090309/download_file?st=MTc0MDE1NDMyOCw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="39728901" href="https://independent.academia.edu/StellaFabiane">Stella Fabiane</a><script data-card-contents-for-user="39728901" type="text/json">{"id":39728901,"first_name":"Stella","last_name":"Fabiane","domain_name":"independent","page_name":"StellaFabiane","display_name":"Stella Fabiane","profile_url":"https://independent.academia.edu/StellaFabiane?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_19453649 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="19453649"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 19453649, container: ".js-paper-rank-work_19453649", }); 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$(".js-view-count[data-work-id=19453649]").text(description); $(".js-view-count-work_19453649").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_19453649").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="19453649"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">7</a>  </div><span class="InlineList-item-text u-textTruncate u-pl9x"><a class="InlineList-item-text" data-has-card-for-ri="28235" rel="nofollow" href="https://www.academia.edu/Documents/in/Multidisciplinary">Multidisciplinary</a>, <script data-card-contents-for-ri="28235" type="text/json">{"id":28235,"name":"Multidisciplinary","url":"https://www.academia.edu/Documents/in/Multidisciplinary?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="33441" rel="nofollow" href="https://www.academia.edu/Documents/in/Macromolecular_X-Ray_Crystallography">Macromolecular X-Ray Crystallography</a>, <script data-card-contents-for-ri="33441" type="text/json">{"id":33441,"name":"Macromolecular X-Ray Crystallography","url":"https://www.academia.edu/Documents/in/Macromolecular_X-Ray_Crystallography?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="176180" rel="nofollow" href="https://www.academia.edu/Documents/in/Immunoglobulin_E">Immunoglobulin E</a>, <script data-card-contents-for-ri="176180" type="text/json">{"id":176180,"name":"Immunoglobulin E","url":"https://www.academia.edu/Documents/in/Immunoglobulin_E?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="678853" rel="nofollow" href="https://www.academia.edu/Documents/in/B_Lymphocytes">B Lymphocytes</a><script data-card-contents-for-ri="678853" type="text/json">{"id":678853,"name":"B Lymphocytes","url":"https://www.academia.edu/Documents/in/B_Lymphocytes?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=19453649]'), work: {"id":19453649,"title":"Crystal structure of IgE bound to its B-cell receptor CD23 reveals a mechanism of reciprocal allosteric inhibition with high affinity receptor Fc RI","created_at":"2015-12-04T02:29:49.468-08:00","url":"https://www.academia.edu/19453649/Crystal_structure_of_IgE_bound_to_its_B_cell_receptor_CD23_reveals_a_mechanism_of_reciprocal_allosteric_inhibition_with_high_affinity_receptor_Fc_RI?f_ri=1970697","dom_id":"work_19453649","summary":"The role of IgE in allergic disease mechanisms is performed principally through its interactions with two receptors, FcεRI on mast cells and basophils, and CD23 (FcεRII) on B cells. The former mediates allergic hypersensitivity, the latter regulates IgE levels, and both receptors, also expressed on antigen-presenting cells, contribute to allergen uptake and presentation to the immune system. We have solved the crystal structure of the soluble lectin-like \u0026amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;head\u0026amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; domain of CD23 (derCD23) bound to a subfragment of IgE-Fc consisting of the dimer of Cε3 and Cε4 domains (Fcε3-4). One CD23 head binds to each heavy chain at the interface between the two domains, explaining the known 2:1 stoichiometry and suggesting mechanisms for cross-linking membrane-bound trimeric CD23 by IgE, or membrane IgE by soluble trimeric forms of CD23, both of which may contribute to the regulation of IgE synthesis by B cells. The two symmetrically located binding sites are distant from the single FcεRI binding site, which lies at the opposite ends of the Cε3 domains. Structural comparisons with both free IgE-Fc and its FcεRI complex reveal not only that the conformational changes in IgE-Fc required for CD23 binding are incompatible with FcεRI binding, but also that the converse is true. The two binding sites are allosterically linked. We demonstrate experimentally the reciprocal inhibition of CD23 and FcεRI binding in solution and suggest that the mutual exclusion of receptor binding allows IgE to function independently through its two receptors.","downloadable_attachments":[{"id":42090309,"asset_id":19453649,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":39728901,"first_name":"Stella","last_name":"Fabiane","domain_name":"independent","page_name":"StellaFabiane","display_name":"Stella Fabiane","profile_url":"https://independent.academia.edu/StellaFabiane?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":28235,"name":"Multidisciplinary","url":"https://www.academia.edu/Documents/in/Multidisciplinary?f_ri=1970697","nofollow":true},{"id":33441,"name":"Macromolecular X-Ray Crystallography","url":"https://www.academia.edu/Documents/in/Macromolecular_X-Ray_Crystallography?f_ri=1970697","nofollow":true},{"id":176180,"name":"Immunoglobulin E","url":"https://www.academia.edu/Documents/in/Immunoglobulin_E?f_ri=1970697","nofollow":true},{"id":678853,"name":"B Lymphocytes","url":"https://www.academia.edu/Documents/in/B_Lymphocytes?f_ri=1970697","nofollow":true},{"id":956752,"name":"Protein Quaternary Structure","url":"https://www.academia.edu/Documents/in/Protein_Quaternary_Structure?f_ri=1970697"},{"id":967839,"name":"Structure activity Relationship","url":"https://www.academia.edu/Documents/in/Structure_activity_Relationship?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_13795417 coauthored" data-work_id="13795417" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/13795417/Evolution_of_allosteric_models_for_hemoglobin">Evolution of allosteric models for hemoglobin</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">We compare various allosteric models that have been proposed to explain cooperative oxygen binding to hemoglobin, including the two-state allosteric model of Monod, Wyman, and Changeux (MWC), the Cooperon model of Brunori, the model of... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_13795417" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">We compare various allosteric models that have been proposed to explain cooperative oxygen binding to hemoglobin, including the two-state allosteric model of Monod, Wyman, and Changeux (MWC), the Cooperon model of Brunori, the model of Szabo and Karplus (SK) based on the stereochemical mechanism of Perutz, the generalization of the SK model by Lee and Karplus (SKL), and the Tertiary Two-State (TTS) model of Henry, Bettati, Hofrichter and Eaton. The preponderance of experimental evidence favors the TTS model which postulates an equilibrium between high (r)-and low (t)affinity tertiary conformations that are present in both the T and R quaternary structures. Cooperative oxygenation in this model arises from the shift of T to R, as in MWC, but with a significant population of both r and t conformations in the liganded T and in the unliganded R quaternary structures. The TTS model may be considered a combination of the SK and SKL models, and these models provide a framework for a structural interpretation of the TTS parameters. The most compelling evidence in favor of the TTS model is the nanosecond -millisecond carbon monoxide (CO) rebinding kinetics in photodissociation experiments on hemoglobin encapsulated in silica gels. The polymeric network of the gel prevents any tertiary or quaternary conformational changes on the sub-second time scale, thereby permitting the subunit conformations prior to CO photodissociation to be determined from their ligand rebinding kinetics. These experiments show that a large fraction of liganded subunits in the T quaternary structure have the same functional conformation as liganded subunits in the R quaternary structure, an experimental finding inconsistent with the MWC, Cooperon, SK, and SKL models, but readily explained by the TTS model as rebinding to r subunits in T. We propose an additional experiment to test another key prediction of the TTS model, namely that a fraction of subunits in the unliganded R quaternary structure has the same functional conformation (t) as unliganded subunits in the T quaternary structure. IUBMB Life, 59: 586-599, 2007</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/13795417" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="61009ecf8670e05bf069adc0f194b2f3" rel="nofollow" data-download="{"attachment_id":44940181,"asset_id":13795417,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/44940181/download_file?st=MTc0MDE1NDMyOCw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="32898141" href="https://unipr.academia.edu/AndreaMozzarelli">Andrea Mozzarelli</a><script data-card-contents-for-user="32898141" type="text/json">{"id":32898141,"first_name":"Andrea","last_name":"Mozzarelli","domain_name":"unipr","page_name":"AndreaMozzarelli","display_name":"Andrea Mozzarelli","profile_url":"https://unipr.academia.edu/AndreaMozzarelli?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span><span class="u-displayInlineBlock InlineList-item-text"> and <span class="u-textDecorationUnderline u-clickable InlineList-item-text js-work-more-authors-13795417">+1</span><div class="hidden js-additional-users-13795417"><div><span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a href="https://unipr.academia.edu/StefanoBettati">Stefano Bettati</a></span></div></div></span><script>(function(){ var popoverSettings = { el: $('.js-work-more-authors-13795417'), placement: 'bottom', hide_delay: 200, html: true, content: function(){ return $('.js-additional-users-13795417').html(); } } new HoverPopover(popoverSettings); })();</script></li><li class="js-paper-rank-work_13795417 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="13795417"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 13795417, container: ".js-paper-rank-work_13795417", }); });</script></li><li class="js-percentile-work_13795417 InlineList-item InlineList-item--bordered hidden u-tcGrayDark"><span class="percentile-widget hidden"><span class="u-mr2x percentile-widget" style="display: none">•</span><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 13795417; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-percentile-work_13795417"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></li><li class="js-view-count-work_13795417 InlineList-item InlineList-item--bordered hidden"><div><span><span class="js-view-count view-count u-mr2x" data-work-id="13795417"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 13795417; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=13795417]").text(description); $(".js-view-count-work_13795417").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_13795417").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="13795417"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">6</a>  </div><span class="InlineList-item-text u-textTruncate u-pl9x"><a class="InlineList-item-text" data-has-card-for-ri="2541" rel="nofollow" href="https://www.academia.edu/Documents/in/Structural_Biology">Structural Biology</a>, <script data-card-contents-for-ri="2541" type="text/json">{"id":2541,"name":"Structural Biology","url":"https://www.academia.edu/Documents/in/Structural_Biology?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="4967" rel="nofollow" href="https://www.academia.edu/Documents/in/Molecular_Evolution">Molecular Evolution</a>, <script data-card-contents-for-ri="4967" type="text/json">{"id":4967,"name":"Molecular Evolution","url":"https://www.academia.edu/Documents/in/Molecular_Evolution?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="166367" rel="nofollow" href="https://www.academia.edu/Documents/in/Protein_structure">Protein structure</a>, <script data-card-contents-for-ri="166367" type="text/json">{"id":166367,"name":"Protein structure","url":"https://www.academia.edu/Documents/in/Protein_structure?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="1311261" rel="nofollow" href="https://www.academia.edu/Documents/in/Hemoglobins">Hemoglobins</a><script data-card-contents-for-ri="1311261" type="text/json">{"id":1311261,"name":"Hemoglobins","url":"https://www.academia.edu/Documents/in/Hemoglobins?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=13795417]'), work: {"id":13795417,"title":"Evolution of allosteric models for hemoglobin","created_at":"2015-07-08T05:09:22.035-07:00","url":"https://www.academia.edu/13795417/Evolution_of_allosteric_models_for_hemoglobin?f_ri=1970697","dom_id":"work_13795417","summary":"We compare various allosteric models that have been proposed to explain cooperative oxygen binding to hemoglobin, including the two-state allosteric model of Monod, Wyman, and Changeux (MWC), the Cooperon model of Brunori, the model of Szabo and Karplus (SK) based on the stereochemical mechanism of Perutz, the generalization of the SK model by Lee and Karplus (SKL), and the Tertiary Two-State (TTS) model of Henry, Bettati, Hofrichter and Eaton. The preponderance of experimental evidence favors the TTS model which postulates an equilibrium between high (r)-and low (t)affinity tertiary conformations that are present in both the T and R quaternary structures. Cooperative oxygenation in this model arises from the shift of T to R, as in MWC, but with a significant population of both r and t conformations in the liganded T and in the unliganded R quaternary structures. The TTS model may be considered a combination of the SK and SKL models, and these models provide a framework for a structural interpretation of the TTS parameters. The most compelling evidence in favor of the TTS model is the nanosecond -millisecond carbon monoxide (CO) rebinding kinetics in photodissociation experiments on hemoglobin encapsulated in silica gels. The polymeric network of the gel prevents any tertiary or quaternary conformational changes on the sub-second time scale, thereby permitting the subunit conformations prior to CO photodissociation to be determined from their ligand rebinding kinetics. These experiments show that a large fraction of liganded subunits in the T quaternary structure have the same functional conformation as liganded subunits in the R quaternary structure, an experimental finding inconsistent with the MWC, Cooperon, SK, and SKL models, but readily explained by the TTS model as rebinding to r subunits in T. We propose an additional experiment to test another key prediction of the TTS model, namely that a fraction of subunits in the unliganded R quaternary structure has the same functional conformation (t) as unliganded subunits in the T quaternary structure. IUBMB Life, 59: 586-599, 2007","downloadable_attachments":[{"id":44940181,"asset_id":13795417,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":32898141,"first_name":"Andrea","last_name":"Mozzarelli","domain_name":"unipr","page_name":"AndreaMozzarelli","display_name":"Andrea Mozzarelli","profile_url":"https://unipr.academia.edu/AndreaMozzarelli?f_ri=1970697","photo":"/images/s65_no_pic.png"},{"id":32956001,"first_name":"Stefano","last_name":"Bettati","domain_name":"unipr","page_name":"StefanoBettati","display_name":"Stefano Bettati","profile_url":"https://unipr.academia.edu/StefanoBettati?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":2541,"name":"Structural Biology","url":"https://www.academia.edu/Documents/in/Structural_Biology?f_ri=1970697","nofollow":true},{"id":4967,"name":"Molecular Evolution","url":"https://www.academia.edu/Documents/in/Molecular_Evolution?f_ri=1970697","nofollow":true},{"id":166367,"name":"Protein structure","url":"https://www.academia.edu/Documents/in/Protein_structure?f_ri=1970697","nofollow":true},{"id":1311261,"name":"Hemoglobins","url":"https://www.academia.edu/Documents/in/Hemoglobins?f_ri=1970697","nofollow":true},{"id":1681026,"name":"Biochemistry and cell biology","url":"https://www.academia.edu/Documents/in/Biochemistry_and_cell_biology?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_50563768" data-work_id="50563768" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/50563768/The_Crystal_Structure_of_Ferritin_from_Helicobacter_pylori_Reveals_Unusual_Conformational_Changes_for_Iron_Uptake">The Crystal Structure of Ferritin from Helicobacter pylori Reveals Unusual Conformational Changes for Iron Uptake</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">The crystal structure of recombinant ferritin from Helicobacter pylori has been determined in its apo, low-iron-bound, intermediate, and high-ironbound states. Similar to other members of the ferritin family, the bacterial ferritin... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_50563768" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">The crystal structure of recombinant ferritin from Helicobacter pylori has been determined in its apo, low-iron-bound, intermediate, and high-ironbound states. Similar to other members of the ferritin family, the bacterial ferritin assembles as a spherical protein shell of 24 subunits, each of which folds into a four-α-helix bundle. Significant conformational changes were observed at the BC loop and the entrance of the 4-fold symmetry channel in the intermediate and high-iron-bound states, whereas no change was found in the apo and low-iron-bound states. The imidazole rings of His149 at the channel entrance undergo conformational changes that bear resemblance to heme configuration and are directly coupled to axial translocation of Fe ions through the 4-fold channel. Our results provide the first structural evidence of the translocation of Fe ions through the 4-fold channel in prokaryotes and the transition from a protein-dominated process to a mineral-surfacedominated process during biomineralization.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/50563768" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="7a97314ece28c26bb831226ae38463de" rel="nofollow" data-download="{"attachment_id":68496938,"asset_id":50563768,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/68496938/download_file?st=MTc0MDE1NDMyOCw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="199868560" href="https://chosun.academia.edu/JungSupLee">Jung Sup Lee</a><script data-card-contents-for-user="199868560" type="text/json">{"id":199868560,"first_name":"Jung Sup","last_name":"Lee","domain_name":"chosun","page_name":"JungSupLee","display_name":"Jung Sup Lee","profile_url":"https://chosun.academia.edu/JungSupLee?f_ri=1970697","photo":"https://0.academia-photos.com/199868560/61488137/49765940/s65_jung_sup.lee.jpeg"}</script></span></span></li><li class="js-paper-rank-work_50563768 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="50563768"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 50563768, container: ".js-paper-rank-work_50563768", }); });</script></li><li class="js-percentile-work_50563768 InlineList-item InlineList-item--bordered hidden u-tcGrayDark"><span class="percentile-widget hidden"><span class="u-mr2x percentile-widget" style="display: none">•</span><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 50563768; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-percentile-work_50563768"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></li><li class="js-view-count-work_50563768 InlineList-item InlineList-item--bordered hidden"><div><span><span class="js-view-count view-count u-mr2x" data-work-id="50563768"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 50563768; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=50563768]").text(description); $(".js-view-count-work_50563768").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_50563768").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="50563768"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">12</a>  </div><span class="InlineList-item-text u-textTruncate u-pl10x"><a class="InlineList-item-text" data-has-card-for-ri="2513" rel="nofollow" href="https://www.academia.edu/Documents/in/Molecular_Biology">Molecular Biology</a>, <script data-card-contents-for-ri="2513" type="text/json">{"id":2513,"name":"Molecular Biology","url":"https://www.academia.edu/Documents/in/Molecular_Biology?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="21460" rel="nofollow" href="https://www.academia.edu/Documents/in/Helicobacter_pylori">Helicobacter pylori</a>, <script data-card-contents-for-ri="21460" type="text/json">{"id":21460,"name":"Helicobacter pylori","url":"https://www.academia.edu/Documents/in/Helicobacter_pylori?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="33441" rel="nofollow" href="https://www.academia.edu/Documents/in/Macromolecular_X-Ray_Crystallography">Macromolecular X-Ray Crystallography</a>, <script data-card-contents-for-ri="33441" type="text/json">{"id":33441,"name":"Macromolecular X-Ray Crystallography","url":"https://www.academia.edu/Documents/in/Macromolecular_X-Ray_Crystallography?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="50157" rel="nofollow" href="https://www.academia.edu/Documents/in/Molecular">Molecular</a><script data-card-contents-for-ri="50157" type="text/json">{"id":50157,"name":"Molecular","url":"https://www.academia.edu/Documents/in/Molecular?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=50563768]'), work: {"id":50563768,"title":"The Crystal Structure of Ferritin from Helicobacter pylori Reveals Unusual Conformational Changes for Iron Uptake","created_at":"2021-08-01T22:49:52.120-07:00","url":"https://www.academia.edu/50563768/The_Crystal_Structure_of_Ferritin_from_Helicobacter_pylori_Reveals_Unusual_Conformational_Changes_for_Iron_Uptake?f_ri=1970697","dom_id":"work_50563768","summary":"The crystal structure of recombinant ferritin from Helicobacter pylori has been determined in its apo, low-iron-bound, intermediate, and high-ironbound states. Similar to other members of the ferritin family, the bacterial ferritin assembles as a spherical protein shell of 24 subunits, each of which folds into a four-α-helix bundle. Significant conformational changes were observed at the BC loop and the entrance of the 4-fold symmetry channel in the intermediate and high-iron-bound states, whereas no change was found in the apo and low-iron-bound states. The imidazole rings of His149 at the channel entrance undergo conformational changes that bear resemblance to heme configuration and are directly coupled to axial translocation of Fe ions through the 4-fold channel. Our results provide the first structural evidence of the translocation of Fe ions through the 4-fold channel in prokaryotes and the transition from a protein-dominated process to a mineral-surfacedominated process during biomineralization.","downloadable_attachments":[{"id":68496938,"asset_id":50563768,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":199868560,"first_name":"Jung Sup","last_name":"Lee","domain_name":"chosun","page_name":"JungSupLee","display_name":"Jung Sup Lee","profile_url":"https://chosun.academia.edu/JungSupLee?f_ri=1970697","photo":"https://0.academia-photos.com/199868560/61488137/49765940/s65_jung_sup.lee.jpeg"}],"research_interests":[{"id":2513,"name":"Molecular Biology","url":"https://www.academia.edu/Documents/in/Molecular_Biology?f_ri=1970697","nofollow":true},{"id":21460,"name":"Helicobacter pylori","url":"https://www.academia.edu/Documents/in/Helicobacter_pylori?f_ri=1970697","nofollow":true},{"id":33441,"name":"Macromolecular X-Ray Crystallography","url":"https://www.academia.edu/Documents/in/Macromolecular_X-Ray_Crystallography?f_ri=1970697","nofollow":true},{"id":50157,"name":"Molecular","url":"https://www.academia.edu/Documents/in/Molecular?f_ri=1970697","nofollow":true},{"id":50630,"name":"Crystal structure","url":"https://www.academia.edu/Documents/in/Crystal_structure?f_ri=1970697"},{"id":158597,"name":"Iron","url":"https://www.academia.edu/Documents/in/Iron?f_ri=1970697"},{"id":555521,"name":"Bound States","url":"https://www.academia.edu/Documents/in/Bound_States?f_ri=1970697"},{"id":956752,"name":"Protein Quaternary Structure","url":"https://www.academia.edu/Documents/in/Protein_Quaternary_Structure?f_ri=1970697"},{"id":1010725,"name":"Protein Binding","url":"https://www.academia.edu/Documents/in/Protein_Binding?f_ri=1970697"},{"id":1274450,"name":"Conformational Change","url":"https://www.academia.edu/Documents/in/Conformational_Change?f_ri=1970697"},{"id":1681026,"name":"Biochemistry and cell biology","url":"https://www.academia.edu/Documents/in/Biochemistry_and_cell_biology?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_1620906 coauthored" data-work_id="1620906" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/1620906/Allosteric_and_orthosteric_sites_in_CC_chemokine_receptor_CCR5_a_chimeric_receptor_approach">Allosteric and orthosteric sites in CC chemokine receptor (CCR5), a chimeric receptor approach</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">Chemokine receptors play a major role in immune system regulation and have consequently been targets for drug development leading to the discovery of several small molecule antagonists. Given the large size and predominantly extracellular... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_1620906" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">Chemokine receptors play a major role in immune system regulation and have consequently been targets for drug development leading to the discovery of several small molecule antagonists. Given the large size and predominantly extracellular receptor interaction of endogenous chemokines, small molecules often act more deeply in an allosteric mode. However, opposed to the well described molecular interaction of allosteric modulators in class C 7-transmembrane helix (7TM) receptors, the interaction in class A, to which the chemokine receptors belong, is more sparsely described. Using the CCR5 chemokine receptor as a model system, we studied the molecular interaction and conformational interchange required for proper action of various orthosteric chemokines and allosteric small molecules, including the well known CCR5 antagonists TAK-779, SCH-C, and aplaviroc, and four novel CCR5 ago-allosteric molecules. A chimera was successfully constructed between CCR5 and the closely related CCR2 by transferring all extracellular regions of CCR2 to CCR5, i.e. a Trojan horse that resembles CCR2 extracellularly but signals through a CCR5 transmembrane unit. The chimera bound CCR2 (CCL2 and CCL7), but not CCR5 chemokines (CCL3 and CCL5), with CCR2-like high affinities and potencies throughout the CCR5 signaling unit. Concomitantly, high affinity binding of small molecule CCR5 agonists and antagonists was retained in the transmembrane region. Importantly, whereas the agonistic and antagonistic properties were preserved, the allosteric enhancement of chemokine binding was disrupted. In summary, the Trojan horse chimera revealed that orthosteric and allosteric sites could be structurally separated and still act together with transmission of agonism and antagonism across the different receptor units.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/1620906" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="1663ee02a6fccdd33ee18de6bcfce5f0" rel="nofollow" data-download="{"attachment_id":50898284,"asset_id":1620906,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/50898284/download_file?st=MTc0MDE1NDMyOCw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="84135" href="https://cambridge.academia.edu/JacekMokrosinski">Jacek Mokrosinski</a><script data-card-contents-for-user="84135" type="text/json">{"id":84135,"first_name":"Jacek","last_name":"Mokrosinski","domain_name":"cambridge","page_name":"JacekMokrosinski","display_name":"Jacek Mokrosinski","profile_url":"https://cambridge.academia.edu/JacekMokrosinski?f_ri=1970697","photo":"https://0.academia-photos.com/84135/84853/8078346/s65_jacek.mokrosinski.jpg"}</script></span></span><span class="u-displayInlineBlock InlineList-item-text"> and <span class="u-textDecorationUnderline u-clickable InlineList-item-text js-work-more-authors-1620906">+1</span><div class="hidden js-additional-users-1620906"><div><span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a href="https://independent.academia.edu/MetteRosenkilde">Mette Rosenkilde</a></span></div></div></span><script>(function(){ var popoverSettings = { el: $('.js-work-more-authors-1620906'), placement: 'bottom', hide_delay: 200, html: true, content: function(){ return $('.js-additional-users-1620906').html(); } } new HoverPopover(popoverSettings); })();</script></li><li class="js-paper-rank-work_1620906 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="1620906"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 1620906, container: ".js-paper-rank-work_1620906", }); });</script></li><li class="js-percentile-work_1620906 InlineList-item InlineList-item--bordered hidden u-tcGrayDark"><span class="percentile-widget hidden"><span class="u-mr2x percentile-widget" style="display: none">•</span><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 1620906; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-percentile-work_1620906"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></li><li class="js-view-count-work_1620906 InlineList-item InlineList-item--bordered hidden"><div><span><span class="js-view-count view-count u-mr2x" data-work-id="1620906"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 1620906; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=1620906]").text(description); $(".js-view-count-work_1620906").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_1620906").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="1620906"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">11</a>  </div><span class="InlineList-item-text u-textTruncate u-pl10x"><a class="InlineList-item-text" data-has-card-for-ri="18520" rel="nofollow" href="https://www.academia.edu/Documents/in/Biological_Chemistry">Biological Chemistry</a>, <script data-card-contents-for-ri="18520" type="text/json">{"id":18520,"name":"Biological Chemistry","url":"https://www.academia.edu/Documents/in/Biological_Chemistry?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="47884" rel="nofollow" href="https://www.academia.edu/Documents/in/Biological_Sciences">Biological Sciences</a>, <script data-card-contents-for-ri="47884" type="text/json">{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="57570" rel="nofollow" href="https://www.academia.edu/Documents/in/Cercopithecus_aethiops">Cercopithecus aethiops</a>, <script data-card-contents-for-ri="57570" type="text/json">{"id":57570,"name":"Cercopithecus aethiops","url":"https://www.academia.edu/Documents/in/Cercopithecus_aethiops?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="117643" rel="nofollow" href="https://www.academia.edu/Documents/in/Biological">Biological</a><script data-card-contents-for-ri="117643" type="text/json">{"id":117643,"name":"Biological","url":"https://www.academia.edu/Documents/in/Biological?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=1620906]'), work: {"id":1620906,"title":"Allosteric and orthosteric sites in CC chemokine receptor (CCR5), a chimeric receptor approach","created_at":"2012-06-04T20:16:52.089-07:00","url":"https://www.academia.edu/1620906/Allosteric_and_orthosteric_sites_in_CC_chemokine_receptor_CCR5_a_chimeric_receptor_approach?f_ri=1970697","dom_id":"work_1620906","summary":"Chemokine receptors play a major role in immune system regulation and have consequently been targets for drug development leading to the discovery of several small molecule antagonists. Given the large size and predominantly extracellular receptor interaction of endogenous chemokines, small molecules often act more deeply in an allosteric mode. However, opposed to the well described molecular interaction of allosteric modulators in class C 7-transmembrane helix (7TM) receptors, the interaction in class A, to which the chemokine receptors belong, is more sparsely described. Using the CCR5 chemokine receptor as a model system, we studied the molecular interaction and conformational interchange required for proper action of various orthosteric chemokines and allosteric small molecules, including the well known CCR5 antagonists TAK-779, SCH-C, and aplaviroc, and four novel CCR5 ago-allosteric molecules. A chimera was successfully constructed between CCR5 and the closely related CCR2 by transferring all extracellular regions of CCR2 to CCR5, i.e. a Trojan horse that resembles CCR2 extracellularly but signals through a CCR5 transmembrane unit. The chimera bound CCR2 (CCL2 and CCL7), but not CCR5 chemokines (CCL3 and CCL5), with CCR2-like high affinities and potencies throughout the CCR5 signaling unit. Concomitantly, high affinity binding of small molecule CCR5 agonists and antagonists was retained in the transmembrane region. Importantly, whereas the agonistic and antagonistic properties were preserved, the allosteric enhancement of chemokine binding was disrupted. In summary, the Trojan horse chimera revealed that orthosteric and allosteric sites could be structurally separated and still act together with transmission of agonism and antagonism across the different receptor units.","downloadable_attachments":[{"id":50898284,"asset_id":1620906,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":84135,"first_name":"Jacek","last_name":"Mokrosinski","domain_name":"cambridge","page_name":"JacekMokrosinski","display_name":"Jacek Mokrosinski","profile_url":"https://cambridge.academia.edu/JacekMokrosinski?f_ri=1970697","photo":"https://0.academia-photos.com/84135/84853/8078346/s65_jacek.mokrosinski.jpg"},{"id":12791526,"first_name":"Mette","last_name":"Rosenkilde","domain_name":"independent","page_name":"MetteRosenkilde","display_name":"Mette Rosenkilde","profile_url":"https://independent.academia.edu/MetteRosenkilde?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":18520,"name":"Biological Chemistry","url":"https://www.academia.edu/Documents/in/Biological_Chemistry?f_ri=1970697","nofollow":true},{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true},{"id":57570,"name":"Cercopithecus aethiops","url":"https://www.academia.edu/Documents/in/Cercopithecus_aethiops?f_ri=1970697","nofollow":true},{"id":117643,"name":"Biological","url":"https://www.academia.edu/Documents/in/Biological?f_ri=1970697","nofollow":true},{"id":260118,"name":"CHEMICAL SCIENCES","url":"https://www.academia.edu/Documents/in/CHEMICAL_SCIENCES?f_ri=1970697"},{"id":362534,"name":"Amides","url":"https://www.academia.edu/Documents/in/Amides?f_ri=1970697"},{"id":490260,"name":"Pyridines","url":"https://www.academia.edu/Documents/in/Pyridines?f_ri=1970697"},{"id":903003,"name":"Chemokines","url":"https://www.academia.edu/Documents/in/Chemokines?f_ri=1970697"},{"id":955937,"name":"Quaternary Ammonium Compounds","url":"https://www.academia.edu/Documents/in/Quaternary_Ammonium_Compounds?f_ri=1970697"},{"id":1880638,"name":"Piperidines","url":"https://www.academia.edu/Documents/in/Piperidines?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_25728598" data-work_id="25728598" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/25728598/Structure_and_control_of_pyridoxal_phosphate_dependent_allosteric_threonine_deaminase">Structure and control of pyridoxal phosphate dependent allosteric threonine deaminase</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">Background: Feedback inhibition of biosynthetic threonine deaminase (TD) from Escherichia coli provided one of the earliest examples of protein-based metabolic regulation. Isoleucine, the pathway end-product, and valine, the product of a... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_25728598" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">Background: Feedback inhibition of biosynthetic threonine deaminase (TD) from Escherichia coli provided one of the earliest examples of protein-based metabolic regulation. Isoleucine, the pathway end-product, and valine, the product of a parallel pathway, serve as allosteric inhibitor and activator, respectively. This enzyme is thus a useful model system for studying the structural basis of allosteric control mechanisms.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/25728598" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="776312818fe40b7c955c8d2e228fb91b" rel="nofollow" data-download="{"attachment_id":46078364,"asset_id":25728598,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/46078364/download_file?st=MTc0MDE1NDMyOCw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="49438597" href="https://independent.academia.edu/EdwardEisenstein">Edward Eisenstein</a><script data-card-contents-for-user="49438597" type="text/json">{"id":49438597,"first_name":"Edward","last_name":"Eisenstein","domain_name":"independent","page_name":"EdwardEisenstein","display_name":"Edward Eisenstein","profile_url":"https://independent.academia.edu/EdwardEisenstein?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_25728598 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="25728598"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 25728598, container: ".js-paper-rank-work_25728598", }); });</script></li><li class="js-percentile-work_25728598 InlineList-item InlineList-item--bordered hidden u-tcGrayDark"><span class="percentile-widget hidden"><span class="u-mr2x percentile-widget" style="display: none">•</span><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 25728598; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-percentile-work_25728598"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></li><li class="js-view-count-work_25728598 InlineList-item InlineList-item--bordered hidden"><div><span><span class="js-view-count view-count u-mr2x" data-work-id="25728598"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 25728598; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=25728598]").text(description); $(".js-view-count-work_25728598").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_25728598").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="25728598"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">19</a>  </div><span class="InlineList-item-text u-textTruncate u-pl10x"><a class="InlineList-item-text" data-has-card-for-ri="3614" rel="nofollow" href="https://www.academia.edu/Documents/in/Structure">Structure</a>, <script data-card-contents-for-ri="3614" type="text/json">{"id":3614,"name":"Structure","url":"https://www.academia.edu/Documents/in/Structure?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="12981" rel="nofollow" href="https://www.academia.edu/Documents/in/Enzyme_Inhibitors">Enzyme Inhibitors</a>, <script data-card-contents-for-ri="12981" type="text/json">{"id":12981,"name":"Enzyme Inhibitors","url":"https://www.academia.edu/Documents/in/Enzyme_Inhibitors?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="33441" rel="nofollow" href="https://www.academia.edu/Documents/in/Macromolecular_X-Ray_Crystallography">Macromolecular X-Ray Crystallography</a>, <script data-card-contents-for-ri="33441" type="text/json">{"id":33441,"name":"Macromolecular X-Ray Crystallography","url":"https://www.academia.edu/Documents/in/Macromolecular_X-Ray_Crystallography?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="47884" rel="nofollow" href="https://www.academia.edu/Documents/in/Biological_Sciences">Biological Sciences</a><script data-card-contents-for-ri="47884" type="text/json">{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=25728598]'), work: {"id":25728598,"title":"Structure and control of pyridoxal phosphate dependent allosteric threonine deaminase","created_at":"2016-05-30T13:17:16.608-07:00","url":"https://www.academia.edu/25728598/Structure_and_control_of_pyridoxal_phosphate_dependent_allosteric_threonine_deaminase?f_ri=1970697","dom_id":"work_25728598","summary":"Background: Feedback inhibition of biosynthetic threonine deaminase (TD) from Escherichia coli provided one of the earliest examples of protein-based metabolic regulation. Isoleucine, the pathway end-product, and valine, the product of a parallel pathway, serve as allosteric inhibitor and activator, respectively. This enzyme is thus a useful model system for studying the structural basis of allosteric control mechanisms.","downloadable_attachments":[{"id":46078364,"asset_id":25728598,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":49438597,"first_name":"Edward","last_name":"Eisenstein","domain_name":"independent","page_name":"EdwardEisenstein","display_name":"Edward Eisenstein","profile_url":"https://independent.academia.edu/EdwardEisenstein?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":3614,"name":"Structure","url":"https://www.academia.edu/Documents/in/Structure?f_ri=1970697","nofollow":true},{"id":12981,"name":"Enzyme Inhibitors","url":"https://www.academia.edu/Documents/in/Enzyme_Inhibitors?f_ri=1970697","nofollow":true},{"id":33441,"name":"Macromolecular X-Ray Crystallography","url":"https://www.academia.edu/Documents/in/Macromolecular_X-Ray_Crystallography?f_ri=1970697","nofollow":true},{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true},{"id":50630,"name":"Crystal structure","url":"https://www.academia.edu/Documents/in/Crystal_structure?f_ri=1970697"},{"id":58496,"name":"Metabolic regulation","url":"https://www.academia.edu/Documents/in/Metabolic_regulation?f_ri=1970697"},{"id":83128,"name":"Escherichia coli","url":"https://www.academia.edu/Documents/in/Escherichia_coli?f_ri=1970697"},{"id":231661,"name":"Enzyme","url":"https://www.academia.edu/Documents/in/Enzyme?f_ri=1970697"},{"id":260118,"name":"CHEMICAL SCIENCES","url":"https://www.academia.edu/Documents/in/CHEMICAL_SCIENCES?f_ri=1970697"},{"id":296798,"name":"Hydrogen Bonding","url":"https://www.academia.edu/Documents/in/Hydrogen_Bonding?f_ri=1970697"},{"id":372917,"name":"Protein Secondary Structure Prediction","url":"https://www.academia.edu/Documents/in/Protein_Secondary_Structure_Prediction?f_ri=1970697"},{"id":434746,"name":"Model System","url":"https://www.academia.edu/Documents/in/Model_System?f_ri=1970697"},{"id":653665,"name":"Protein Conformation","url":"https://www.academia.edu/Documents/in/Protein_Conformation?f_ri=1970697"},{"id":967839,"name":"Structure activity Relationship","url":"https://www.academia.edu/Documents/in/Structure_activity_Relationship?f_ri=1970697"},{"id":1011864,"name":"Structure Function","url":"https://www.academia.edu/Documents/in/Structure_Function?f_ri=1970697"},{"id":1242506,"name":"Binding Site","url":"https://www.academia.edu/Documents/in/Binding_Site?f_ri=1970697"},{"id":1582300,"name":"Pyridoxal Phosphate","url":"https://www.academia.edu/Documents/in/Pyridoxal_Phosphate?f_ri=1970697"},{"id":1809037,"name":"Dimerization","url":"https://www.academia.edu/Documents/in/Dimerization?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_3833787" data-work_id="3833787" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/3833787/Allosteric_Regulation_of_Glycogen_Synthase_Controls_Glycogen_Synthesis_in_Muscle">Allosteric Regulation of Glycogen Synthase Controls Glycogen Synthesis in Muscle</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">Glycogen synthase (GS), a key enzyme in glycogen synthesis, is activated by the allosteric stimulator glucose-6-phosphate (G6P) and by dephosphorylation through inactivation of GS kinase-3 with insulin. The relative importance of these... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_3833787" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">Glycogen synthase (GS), a key enzyme in glycogen synthesis, is activated by the allosteric stimulator glucose-6-phosphate (G6P) and by dephosphorylation through inactivation of GS kinase-3 with insulin. The relative importance of these two regulatory mechanisms in controlling GS is not established, mainly due to the complex interplay between multiple phosphorylation sites and allosteric effectors. Here we identify a residue that plays an important role in the allosteric activation of GS by G6P. We generated knockin mice in which wild-type muscle GS was replaced by a mutant that could not be activated by G6P but could still be activated normally by dephosphorylation. We demonstrate that knockin mice expressing the G6P-insensitive mutant display an ∼80% reduced muscle glycogen synthesis by insulin and markedly reduced glycogen levels. Our study provides genetic evidence that allosteric activation of GS is the primary mechanism by which insulin promotes muscle glycogen accumulation in vivo.► A critical glucose-6-phosphate (G6P) action site on glycogen synthase (GS) identified ► A knockin mouse expressing G6P-insensitive mutant GS generated ► GS knockin mice display dramatically reduced ability to accumulate muscle glycogen ► Insulin promotes glycogen synthesis mainly via allosteric activation of GS by G6P</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/3833787" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="615dc1b0a08fa60d286125f306db5244" rel="nofollow" data-download="{"attachment_id":50121259,"asset_id":3833787,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/50121259/download_file?st=MTc0MDE1NDMyOCw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="4716765" href="https://dundee.academia.edu/MichaleBouskila">Michale Bouskila</a><script data-card-contents-for-user="4716765" type="text/json">{"id":4716765,"first_name":"Michale","last_name":"Bouskila","domain_name":"dundee","page_name":"MichaleBouskila","display_name":"Michale Bouskila","profile_url":"https://dundee.academia.edu/MichaleBouskila?f_ri=1970697","photo":"https://0.academia-photos.com/4716765/1992768/2352432/s65_michale.bouskila.jpg"}</script></span></span></li><li class="js-paper-rank-work_3833787 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="3833787"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 3833787, container: ".js-paper-rank-work_3833787", }); 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$(".js-view-count[data-work-id=3833787]").text(description); $(".js-view-count-work_3833787").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_3833787").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="3833787"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">9</a>  </div><span class="InlineList-item-text u-textTruncate u-pl9x"><a class="InlineList-item-text" data-has-card-for-ri="57808" rel="nofollow" href="https://www.academia.edu/Documents/in/Cell_line">Cell line</a>, <script data-card-contents-for-ri="57808" type="text/json">{"id":57808,"name":"Cell line","url":"https://www.academia.edu/Documents/in/Cell_line?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="71289" rel="nofollow" href="https://www.academia.edu/Documents/in/Glucose">Glucose</a>, <script data-card-contents-for-ri="71289" type="text/json">{"id":71289,"name":"Glucose","url":"https://www.academia.edu/Documents/in/Glucose?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="71400" rel="nofollow" href="https://www.academia.edu/Documents/in/Insulin">Insulin</a>, <script data-card-contents-for-ri="71400" type="text/json">{"id":71400,"name":"Insulin","url":"https://www.academia.edu/Documents/in/Insulin?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="74780" rel="nofollow" href="https://www.academia.edu/Documents/in/Mutation">Mutation</a><script data-card-contents-for-ri="74780" type="text/json">{"id":74780,"name":"Mutation","url":"https://www.academia.edu/Documents/in/Mutation?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=3833787]'), work: {"id":3833787,"title":"Allosteric Regulation of Glycogen Synthase Controls Glycogen Synthesis in Muscle","created_at":"2013-07-01T17:54:15.880-07:00","url":"https://www.academia.edu/3833787/Allosteric_Regulation_of_Glycogen_Synthase_Controls_Glycogen_Synthesis_in_Muscle?f_ri=1970697","dom_id":"work_3833787","summary":"Glycogen synthase (GS), a key enzyme in glycogen synthesis, is activated by the allosteric stimulator glucose-6-phosphate (G6P) and by dephosphorylation through inactivation of GS kinase-3 with insulin. The relative importance of these two regulatory mechanisms in controlling GS is not established, mainly due to the complex interplay between multiple phosphorylation sites and allosteric effectors. Here we identify a residue that plays an important role in the allosteric activation of GS by G6P. We generated knockin mice in which wild-type muscle GS was replaced by a mutant that could not be activated by G6P but could still be activated normally by dephosphorylation. We demonstrate that knockin mice expressing the G6P-insensitive mutant display an ∼80% reduced muscle glycogen synthesis by insulin and markedly reduced glycogen levels. Our study provides genetic evidence that allosteric activation of GS is the primary mechanism by which insulin promotes muscle glycogen accumulation in vivo.► A critical glucose-6-phosphate (G6P) action site on glycogen synthase (GS) identified ► A knockin mouse expressing G6P-insensitive mutant GS generated ► GS knockin mice display dramatically reduced ability to accumulate muscle glycogen ► Insulin promotes glycogen synthesis mainly via allosteric activation of GS by G6P","downloadable_attachments":[{"id":50121259,"asset_id":3833787,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":4716765,"first_name":"Michale","last_name":"Bouskila","domain_name":"dundee","page_name":"MichaleBouskila","display_name":"Michale Bouskila","profile_url":"https://dundee.academia.edu/MichaleBouskila?f_ri=1970697","photo":"https://0.academia-photos.com/4716765/1992768/2352432/s65_michale.bouskila.jpg"}],"research_interests":[{"id":57808,"name":"Cell line","url":"https://www.academia.edu/Documents/in/Cell_line?f_ri=1970697","nofollow":true},{"id":71289,"name":"Glucose","url":"https://www.academia.edu/Documents/in/Glucose?f_ri=1970697","nofollow":true},{"id":71400,"name":"Insulin","url":"https://www.academia.edu/Documents/in/Insulin?f_ri=1970697","nofollow":true},{"id":74780,"name":"Mutation","url":"https://www.academia.edu/Documents/in/Mutation?f_ri=1970697","nofollow":true},{"id":84760,"name":"Mice","url":"https://www.academia.edu/Documents/in/Mice?f_ri=1970697"},{"id":134095,"name":"Muscles","url":"https://www.academia.edu/Documents/in/Muscles?f_ri=1970697"},{"id":1232429,"name":"Glycogen","url":"https://www.academia.edu/Documents/in/Glycogen?f_ri=1970697"},{"id":1681026,"name":"Biochemistry and cell biology","url":"https://www.academia.edu/Documents/in/Biochemistry_and_cell_biology?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_24100614" data-work_id="24100614" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/24100614/A_Novel_%CE%B15GABAAR_Positive_Allosteric_Modulator_Reverses_Hyperactivation_of_the_Dopamine_System_in_the_MAM_Model_of_Schizophrenia">A Novel α5GABAAR-Positive Allosteric Modulator Reverses Hyperactivation of the Dopamine System in the MAM Model of Schizophrenia</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">We have shown previously that aberrant hippocampal (HPC) output underlies the dopamine (DA) dysfunction observed in the methylazoxymethanol acetate (MAM) developmental model of schizophrenia in the rodent. This alteration of HPC activity... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_24100614" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">We have shown previously that aberrant hippocampal (HPC) output underlies the dopamine (DA) dysfunction observed in the methylazoxymethanol acetate (MAM) developmental model of schizophrenia in the rodent. This alteration of HPC activity was proposed to result from a reduction in parvalbumin (PV)-expressing GABAergic interneurons and consequent destabilization of the output of pyramidal neurons, as well as disrupted activation across a broad neural network. In vivo extracellular recordings were performed in the ventral tegmental area (VTA) and ventral HPC of saline-(SAL) and MAM-treated animals. A novel benzodiazepine-positive allosteric modulator (PAM), selective for the a5 subunit of the GABA A receptor, SH-053-2 0 F-R-CH3, was tested for its effects on the output of the HPC, leading to dopamine system hyperactivity in MAM-treated animals. In addition, the effect of SH-053-2 0 F-R-CH3 on the hyperactive locomotor response to amphetamine in MAM animals was examined. We demonstrate that treatment with the a5GABA A R PAM reduced the number of spontaneously active DA neurons in the VTA of MAM animals to levels observed in SAL rats, both when administered systemically and when directly infused into the ventral HPC. Moreover, HPC neurons in both SAL and MAM animals showed diminished cortical-evoked responses following a5GABA A R PAM treatment. In addition, the increased locomotor response to amphetamine observed in MAM rats was reduced following a5GABA A R treatment. This study supports a novel treatment of schizophrenia that targets abnormal HPC output, which in turn normalizes dopaminergic neuronal activity.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/24100614" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="32a2267e0641d5532fa2686fd1afa837" rel="nofollow" data-download="{"attachment_id":44465058,"asset_id":24100614,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/44465058/download_file?st=MTc0MDE1NDMyOCw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="32640672" href="https://independent.academia.edu/AnthonyGrace1">Anthony Grace</a><script data-card-contents-for-user="32640672" type="text/json">{"id":32640672,"first_name":"Anthony","last_name":"Grace","domain_name":"independent","page_name":"AnthonyGrace1","display_name":"Anthony Grace","profile_url":"https://independent.academia.edu/AnthonyGrace1?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_24100614 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="24100614"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 24100614, container: ".js-paper-rank-work_24100614", }); });</script></li><li class="js-percentile-work_24100614 InlineList-item InlineList-item--bordered hidden u-tcGrayDark"><span class="percentile-widget hidden"><span class="u-mr2x percentile-widget" style="display: none">•</span><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 24100614; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-percentile-work_24100614"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></li><li class="js-view-count-work_24100614 InlineList-item InlineList-item--bordered hidden"><div><span><span class="js-view-count view-count u-mr2x" data-work-id="24100614"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 24100614; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=24100614]").text(description); $(".js-view-count-work_24100614").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_24100614").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="24100614"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">16</a>  </div><span class="InlineList-item-text u-textTruncate u-pl10x"><a class="InlineList-item-text" data-has-card-for-ri="3227" rel="nofollow" href="https://www.academia.edu/Documents/in/Schizophrenia">Schizophrenia</a>, <script data-card-contents-for-ri="3227" type="text/json">{"id":3227,"name":"Schizophrenia","url":"https://www.academia.edu/Documents/in/Schizophrenia?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="10115" rel="nofollow" href="https://www.academia.edu/Documents/in/Neuropsychopharmacology">Neuropsychopharmacology</a>, <script data-card-contents-for-ri="10115" type="text/json">{"id":10115,"name":"Neuropsychopharmacology","url":"https://www.academia.edu/Documents/in/Neuropsychopharmacology?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="26066" rel="nofollow" href="https://www.academia.edu/Documents/in/Neural_Network">Neural Network</a>, <script data-card-contents-for-ri="26066" type="text/json">{"id":26066,"name":"Neural Network","url":"https://www.academia.edu/Documents/in/Neural_Network?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="51566" rel="nofollow" href="https://www.academia.edu/Documents/in/Dopamine">Dopamine</a><script data-card-contents-for-ri="51566" type="text/json">{"id":51566,"name":"Dopamine","url":"https://www.academia.edu/Documents/in/Dopamine?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=24100614]'), work: {"id":24100614,"title":"A Novel α5GABAAR-Positive Allosteric Modulator Reverses Hyperactivation of the Dopamine System in the MAM Model of Schizophrenia","created_at":"2016-04-06T00:33:10.304-07:00","url":"https://www.academia.edu/24100614/A_Novel_%CE%B15GABAAR_Positive_Allosteric_Modulator_Reverses_Hyperactivation_of_the_Dopamine_System_in_the_MAM_Model_of_Schizophrenia?f_ri=1970697","dom_id":"work_24100614","summary":"We have shown previously that aberrant hippocampal (HPC) output underlies the dopamine (DA) dysfunction observed in the methylazoxymethanol acetate (MAM) developmental model of schizophrenia in the rodent. This alteration of HPC activity was proposed to result from a reduction in parvalbumin (PV)-expressing GABAergic interneurons and consequent destabilization of the output of pyramidal neurons, as well as disrupted activation across a broad neural network. In vivo extracellular recordings were performed in the ventral tegmental area (VTA) and ventral HPC of saline-(SAL) and MAM-treated animals. A novel benzodiazepine-positive allosteric modulator (PAM), selective for the a5 subunit of the GABA A receptor, SH-053-2 0 F-R-CH3, was tested for its effects on the output of the HPC, leading to dopamine system hyperactivity in MAM-treated animals. In addition, the effect of SH-053-2 0 F-R-CH3 on the hyperactive locomotor response to amphetamine in MAM animals was examined. We demonstrate that treatment with the a5GABA A R PAM reduced the number of spontaneously active DA neurons in the VTA of MAM animals to levels observed in SAL rats, both when administered systemically and when directly infused into the ventral HPC. Moreover, HPC neurons in both SAL and MAM animals showed diminished cortical-evoked responses following a5GABA A R PAM treatment. In addition, the increased locomotor response to amphetamine observed in MAM rats was reduced following a5GABA A R treatment. This study supports a novel treatment of schizophrenia that targets abnormal HPC output, which in turn normalizes dopaminergic neuronal activity.","downloadable_attachments":[{"id":44465058,"asset_id":24100614,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":32640672,"first_name":"Anthony","last_name":"Grace","domain_name":"independent","page_name":"AnthonyGrace1","display_name":"Anthony Grace","profile_url":"https://independent.academia.edu/AnthonyGrace1?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":3227,"name":"Schizophrenia","url":"https://www.academia.edu/Documents/in/Schizophrenia?f_ri=1970697","nofollow":true},{"id":10115,"name":"Neuropsychopharmacology","url":"https://www.academia.edu/Documents/in/Neuropsychopharmacology?f_ri=1970697","nofollow":true},{"id":26066,"name":"Neural Network","url":"https://www.academia.edu/Documents/in/Neural_Network?f_ri=1970697","nofollow":true},{"id":51566,"name":"Dopamine","url":"https://www.academia.edu/Documents/in/Dopamine?f_ri=1970697","nofollow":true},{"id":57556,"name":"Hippocampus","url":"https://www.academia.edu/Documents/in/Hippocampus?f_ri=1970697"},{"id":62550,"name":"Pregnancy","url":"https://www.academia.edu/Documents/in/Pregnancy?f_ri=1970697"},{"id":121706,"name":"Amphetamine","url":"https://www.academia.edu/Documents/in/Amphetamine?f_ri=1970697"},{"id":133351,"name":"Benzodiazepines","url":"https://www.academia.edu/Documents/in/Benzodiazepines?f_ri=1970697"},{"id":239480,"name":"Neurotoxins","url":"https://www.academia.edu/Documents/in/Neurotoxins?f_ri=1970697"},{"id":375054,"name":"Rats","url":"https://www.academia.edu/Documents/in/Rats?f_ri=1970697"},{"id":665545,"name":"Hyperkinesis","url":"https://www.academia.edu/Documents/in/Hyperkinesis?f_ri=1970697"},{"id":767927,"name":"Ventral Tegmental Area","url":"https://www.academia.edu/Documents/in/Ventral_Tegmental_Area?f_ri=1970697"},{"id":801409,"name":"Imidazoles","url":"https://www.academia.edu/Documents/in/Imidazoles?f_ri=1970697"},{"id":853012,"name":"Diazepam","url":"https://www.academia.edu/Documents/in/Diazepam?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"},{"id":2111545,"name":"Spontaneous Activity","url":"https://www.academia.edu/Documents/in/Spontaneous_Activity?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_19790859" data-work_id="19790859" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/19790859/Recent_advances_in_understanding_GLP_1R_glucagon_like_peptide_1_receptor_function">Recent advances in understanding GLP-1R (glucagon-like peptide-1 receptor) function</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">Type 2 diabetes is a major global health problem and there is ongoing research for new treatments to manage the disease. The GLP-1R (glucagon-like peptide-1 receptor) controls the physiological response to the incretin peptide, GLP-1, and... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_19790859" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">Type 2 diabetes is a major global health problem and there is ongoing research for new treatments to manage the disease. The GLP-1R (glucagon-like peptide-1 receptor) controls the physiological response to the incretin peptide, GLP-1, and is currently a major target for the development of therapeutics owing to the broad range of potential beneficial effects in Type 2 diabetes. These include promotion of glucose-dependent insulin secretion, increased insulin biosynthesis, preservation of β-cell mass, improved peripheral insulin sensitivity and promotion of weight loss. Despite this, our understanding of GLP-1R function is still limited, with the desired spectrum of GLP-1R-mediated signalling yet to be determined. We review the current understanding of GLP-1R function, in particular, highlighting recent contributions in the field on allosteric modulation, probe-dependence and ligand-directed signal bias and how these behaviours may influence future drug development.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/19790859" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="152fb1c275cf2db5b72493ddea89490d" rel="nofollow" data-download="{"attachment_id":42016824,"asset_id":19790859,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/42016824/download_file?st=MTc0MDE1NDMyOCw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="40521139" href="https://independent.academia.edu/WoottenDenise">Denise Wootten</a><script data-card-contents-for-user="40521139" type="text/json">{"id":40521139,"first_name":"Denise","last_name":"Wootten","domain_name":"independent","page_name":"WoottenDenise","display_name":"Denise Wootten","profile_url":"https://independent.academia.edu/WoottenDenise?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_19790859 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="19790859"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 19790859, container: ".js-paper-rank-work_19790859", }); });</script></li><li class="js-percentile-work_19790859 InlineList-item InlineList-item--bordered hidden u-tcGrayDark"><span class="percentile-widget hidden"><span class="u-mr2x percentile-widget" style="display: none">•</span><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 19790859; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-percentile-work_19790859"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></li><li class="js-view-count-work_19790859 InlineList-item InlineList-item--bordered hidden"><div><span><span class="js-view-count view-count u-mr2x" data-work-id="19790859"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 19790859; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=19790859]").text(description); $(".js-view-count-work_19790859").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_19790859").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="19790859"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">7</a>  </div><span class="InlineList-item-text u-textTruncate u-pl9x"><a class="InlineList-item-text" data-has-card-for-ri="38831" rel="nofollow" href="https://www.academia.edu/Documents/in/Signal_Transduction">Signal Transduction</a>, <script data-card-contents-for-ri="38831" type="text/json">{"id":38831,"name":"Signal Transduction","url":"https://www.academia.edu/Documents/in/Signal_Transduction?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="383939" rel="nofollow" href="https://www.academia.edu/Documents/in/Molecular_Mimicry">Molecular Mimicry</a>, <script data-card-contents-for-ri="383939" type="text/json">{"id":383939,"name":"Molecular Mimicry","url":"https://www.academia.edu/Documents/in/Molecular_Mimicry?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="809881" rel="nofollow" href="https://www.academia.edu/Documents/in/Amino_Acid_Sequence">Amino Acid Sequence</a>, <script data-card-contents-for-ri="809881" type="text/json">{"id":809881,"name":"Amino Acid Sequence","url":"https://www.academia.edu/Documents/in/Amino_Acid_Sequence?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="915951" rel="nofollow" href="https://www.academia.edu/Documents/in/Type_2_Diabetes_Mellitus">Type 2 Diabetes Mellitus</a><script data-card-contents-for-ri="915951" type="text/json">{"id":915951,"name":"Type 2 Diabetes Mellitus","url":"https://www.academia.edu/Documents/in/Type_2_Diabetes_Mellitus?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=19790859]'), work: {"id":19790859,"title":"Recent advances in understanding GLP-1R (glucagon-like peptide-1 receptor) function","created_at":"2015-12-22T14:03:33.820-08:00","url":"https://www.academia.edu/19790859/Recent_advances_in_understanding_GLP_1R_glucagon_like_peptide_1_receptor_function?f_ri=1970697","dom_id":"work_19790859","summary":"Type 2 diabetes is a major global health problem and there is ongoing research for new treatments to manage the disease. The GLP-1R (glucagon-like peptide-1 receptor) controls the physiological response to the incretin peptide, GLP-1, and is currently a major target for the development of therapeutics owing to the broad range of potential beneficial effects in Type 2 diabetes. These include promotion of glucose-dependent insulin secretion, increased insulin biosynthesis, preservation of β-cell mass, improved peripheral insulin sensitivity and promotion of weight loss. Despite this, our understanding of GLP-1R function is still limited, with the desired spectrum of GLP-1R-mediated signalling yet to be determined. We review the current understanding of GLP-1R function, in particular, highlighting recent contributions in the field on allosteric modulation, probe-dependence and ligand-directed signal bias and how these behaviours may influence future drug development.","downloadable_attachments":[{"id":42016824,"asset_id":19790859,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":40521139,"first_name":"Denise","last_name":"Wootten","domain_name":"independent","page_name":"WoottenDenise","display_name":"Denise Wootten","profile_url":"https://independent.academia.edu/WoottenDenise?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":38831,"name":"Signal Transduction","url":"https://www.academia.edu/Documents/in/Signal_Transduction?f_ri=1970697","nofollow":true},{"id":383939,"name":"Molecular Mimicry","url":"https://www.academia.edu/Documents/in/Molecular_Mimicry?f_ri=1970697","nofollow":true},{"id":809881,"name":"Amino Acid Sequence","url":"https://www.academia.edu/Documents/in/Amino_Acid_Sequence?f_ri=1970697","nofollow":true},{"id":915951,"name":"Type 2 Diabetes Mellitus","url":"https://www.academia.edu/Documents/in/Type_2_Diabetes_Mellitus?f_ri=1970697","nofollow":true},{"id":1681026,"name":"Biochemistry and cell biology","url":"https://www.academia.edu/Documents/in/Biochemistry_and_cell_biology?f_ri=1970697"},{"id":1826365,"name":"Incretins","url":"https://www.academia.edu/Documents/in/Incretins?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_21180567" data-work_id="21180567" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/21180567/Muscarinic_acetylcholine_receptors_novel_opportunities_for_drug_development">Muscarinic acetylcholine receptors: novel opportunities for drug development</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">The muscarinic acetylcholine receptors (mAChRs) comprise a family of five related G protein-coupled receptors (GPCRs) belonging to the α-branch of class A GPCRs 1 . The mAChR family consists of five distinct subtypes, denoted M 1 to M 5... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_21180567" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">The muscarinic acetylcholine receptors (mAChRs) comprise a family of five related G protein-coupled receptors (GPCRs) belonging to the α-branch of class A GPCRs 1 . The mAChR family consists of five distinct subtypes, denoted M 1 to M 5 (and encoded by the genes CHRM1 to CHRM5). Three of these receptor subtypes (M 1 , M 3 and M 5 ) have been shown to couple to G proteins of the G q/11 family, whereas the remaining two subtypes (M 2 and M 4 ) preferentially signal through the G i/o family of G proteins 2 . The mAChRs have a central role in human physiology, regulating heart rate, smooth muscle contraction, glandular secretion and many fundamental functions of the central nervous system (CNS) 3 .</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/21180567" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="3fc60ab8497ddd4b2e75870f4befbcff" rel="nofollow" data-download="{"attachment_id":41750645,"asset_id":21180567,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/41750645/download_file?st=MTc0MDE1NDMyOCw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="42344825" href="https://independent.academia.edu/DineshGautam7">Dinesh Gautam</a><script data-card-contents-for-user="42344825" type="text/json">{"id":42344825,"first_name":"Dinesh","last_name":"Gautam","domain_name":"independent","page_name":"DineshGautam7","display_name":"Dinesh Gautam","profile_url":"https://independent.academia.edu/DineshGautam7?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_21180567 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="21180567"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 21180567, container: ".js-paper-rank-work_21180567", }); });</script></li><li class="js-percentile-work_21180567 InlineList-item InlineList-item--bordered hidden u-tcGrayDark"><span class="percentile-widget hidden"><span class="u-mr2x percentile-widget" style="display: none">•</span><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 21180567; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-percentile-work_21180567"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></li><li class="js-view-count-work_21180567 InlineList-item InlineList-item--bordered hidden"><div><span><span class="js-view-count view-count u-mr2x" data-work-id="21180567"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 21180567; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=21180567]").text(description); $(".js-view-count-work_21180567").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_21180567").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="21180567"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">4</a>  </div><span class="InlineList-item-text u-textTruncate u-pl9x"><a class="InlineList-item-text" data-has-card-for-ri="47884" rel="nofollow" href="https://www.academia.edu/Documents/in/Biological_Sciences">Biological Sciences</a>, <script data-card-contents-for-ri="47884" type="text/json">{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="469018" rel="nofollow" href="https://www.academia.edu/Documents/in/Neoplasms">Neoplasms</a>, <script data-card-contents-for-ri="469018" type="text/json">{"id":469018,"name":"Neoplasms","url":"https://www.academia.edu/Documents/in/Neoplasms?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="915951" rel="nofollow" href="https://www.academia.edu/Documents/in/Type_2_Diabetes_Mellitus">Type 2 Diabetes Mellitus</a>, <script data-card-contents-for-ri="915951" type="text/json">{"id":915951,"name":"Type 2 Diabetes Mellitus","url":"https://www.academia.edu/Documents/in/Type_2_Diabetes_Mellitus?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="1970697" rel="nofollow" href="https://www.academia.edu/Documents/in/Allosteric_regulation">Allosteric regulation</a><script data-card-contents-for-ri="1970697" type="text/json">{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=21180567]'), work: {"id":21180567,"title":"Muscarinic acetylcholine receptors: novel opportunities for drug development","created_at":"2016-01-29T13:32:11.149-08:00","url":"https://www.academia.edu/21180567/Muscarinic_acetylcholine_receptors_novel_opportunities_for_drug_development?f_ri=1970697","dom_id":"work_21180567","summary":"The muscarinic acetylcholine receptors (mAChRs) comprise a family of five related G protein-coupled receptors (GPCRs) belonging to the α-branch of class A GPCRs 1 . The mAChR family consists of five distinct subtypes, denoted M 1 to M 5 (and encoded by the genes CHRM1 to CHRM5). Three of these receptor subtypes (M 1 , M 3 and M 5 ) have been shown to couple to G proteins of the G q/11 family, whereas the remaining two subtypes (M 2 and M 4 ) preferentially signal through the G i/o family of G proteins 2 . The mAChRs have a central role in human physiology, regulating heart rate, smooth muscle contraction, glandular secretion and many fundamental functions of the central nervous system (CNS) 3 .","downloadable_attachments":[{"id":41750645,"asset_id":21180567,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":42344825,"first_name":"Dinesh","last_name":"Gautam","domain_name":"independent","page_name":"DineshGautam7","display_name":"Dinesh Gautam","profile_url":"https://independent.academia.edu/DineshGautam7?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true},{"id":469018,"name":"Neoplasms","url":"https://www.academia.edu/Documents/in/Neoplasms?f_ri=1970697","nofollow":true},{"id":915951,"name":"Type 2 Diabetes Mellitus","url":"https://www.academia.edu/Documents/in/Type_2_Diabetes_Mellitus?f_ri=1970697","nofollow":true},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697","nofollow":true}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_6134383" data-work_id="6134383" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/6134383/The_discovery_and_optimization_of_hexahydro_2_H_pyrano_3_2_c_quinolines_HHPQs_as_potent_and_selective_inhibitors_of_the_mitotic_kinesin_5">The discovery and optimization of hexahydro-2 H-pyrano[3,2- c]quinolines (HHPQs) as potent and selective inhibitors of the mitotic kinesin-5</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">Here we describe the discovery and optimization of hexahydro-2H-pyrano[3,2-c]quinolines (HHPQs) as potent and selective inhibitors of the mitotic kinesin-5 originally found during a high-throughput screening (HTS) campaign sampling our... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_6134383" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">Here we describe the discovery and optimization of hexahydro-2H-pyrano[3,2-c]quinolines (HHPQs) as potent and selective inhibitors of the mitotic kinesin-5 originally found during a high-throughput screening (HTS) campaign sampling our in-house compound collection. The compounds optimized subsequently and characterized herein were potently inhibiting the ATPase activity of Kinesin-5 and also exhibited consistent cellular activity, in that cells arrested in mitosis and apoptosis induction could be observed. X-ray crystallographic data demonstrated that these inhibitors bind in an allosteric pocket of Kinesin-5 distant from the nucleotide and microtubule binding sites. The selected clinical candidate EMD 534085 caused strong growth inhibition in human tumor xenograft models using Colo 205 colon carcinoma cells at doses below 30 mg/kg administered twice weekly without showing severe toxicity as determined by loss of body weight.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/6134383" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="eec9a3511ad0fb80ddb68d88ec023cbe" rel="nofollow" data-download="{"attachment_id":49004185,"asset_id":6134383,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/49004185/download_file?st=MTc0MDE1NDMyOCw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="9303745" href="https://independent.academia.edu/davidbruges">david bruges</a><script data-card-contents-for-user="9303745" type="text/json">{"id":9303745,"first_name":"david","last_name":"bruges","domain_name":"independent","page_name":"davidbruges","display_name":"david bruges","profile_url":"https://independent.academia.edu/davidbruges?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_6134383 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="6134383"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 6134383, container: ".js-paper-rank-work_6134383", }); });</script></li><li class="js-percentile-work_6134383 InlineList-item InlineList-item--bordered hidden u-tcGrayDark"><span class="percentile-widget hidden"><span class="u-mr2x percentile-widget" style="display: none">•</span><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 6134383; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-percentile-work_6134383"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></li><li class="js-view-count-work_6134383 InlineList-item InlineList-item--bordered hidden"><div><span><span class="js-view-count view-count u-mr2x" data-work-id="6134383"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 6134383; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=6134383]").text(description); $(".js-view-count-work_6134383").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_6134383").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="6134383"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">19</a>  </div><span class="InlineList-item-text u-textTruncate u-pl10x"><a class="InlineList-item-text" data-has-card-for-ri="531" rel="nofollow" href="https://www.academia.edu/Documents/in/Organic_Chemistry">Organic Chemistry</a>, <script data-card-contents-for-ri="531" type="text/json">{"id":531,"name":"Organic Chemistry","url":"https://www.academia.edu/Documents/in/Organic_Chemistry?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="10640" rel="nofollow" href="https://www.academia.edu/Documents/in/Drug_Discovery">Drug Discovery</a>, <script data-card-contents-for-ri="10640" type="text/json">{"id":10640,"name":"Drug Discovery","url":"https://www.academia.edu/Documents/in/Drug_Discovery?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="12981" rel="nofollow" href="https://www.academia.edu/Documents/in/Enzyme_Inhibitors">Enzyme Inhibitors</a>, <script data-card-contents-for-ri="12981" type="text/json">{"id":12981,"name":"Enzyme Inhibitors","url":"https://www.academia.edu/Documents/in/Enzyme_Inhibitors?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="33441" rel="nofollow" href="https://www.academia.edu/Documents/in/Macromolecular_X-Ray_Crystallography">Macromolecular X-Ray Crystallography</a><script data-card-contents-for-ri="33441" type="text/json">{"id":33441,"name":"Macromolecular X-Ray Crystallography","url":"https://www.academia.edu/Documents/in/Macromolecular_X-Ray_Crystallography?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=6134383]'), work: {"id":6134383,"title":"The discovery and optimization of hexahydro-2 H-pyrano[3,2- c]quinolines (HHPQs) as potent and selective inhibitors of the mitotic kinesin-5","created_at":"2014-02-19T04:57:17.597-08:00","url":"https://www.academia.edu/6134383/The_discovery_and_optimization_of_hexahydro_2_H_pyrano_3_2_c_quinolines_HHPQs_as_potent_and_selective_inhibitors_of_the_mitotic_kinesin_5?f_ri=1970697","dom_id":"work_6134383","summary":"Here we describe the discovery and optimization of hexahydro-2H-pyrano[3,2-c]quinolines (HHPQs) as potent and selective inhibitors of the mitotic kinesin-5 originally found during a high-throughput screening (HTS) campaign sampling our in-house compound collection. The compounds optimized subsequently and characterized herein were potently inhibiting the ATPase activity of Kinesin-5 and also exhibited consistent cellular activity, in that cells arrested in mitosis and apoptosis induction could be observed. X-ray crystallographic data demonstrated that these inhibitors bind in an allosteric pocket of Kinesin-5 distant from the nucleotide and microtubule binding sites. The selected clinical candidate EMD 534085 caused strong growth inhibition in human tumor xenograft models using Colo 205 colon carcinoma cells at doses below 30 mg/kg administered twice weekly without showing severe toxicity as determined by loss of body weight.","downloadable_attachments":[{"id":49004185,"asset_id":6134383,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":9303745,"first_name":"david","last_name":"bruges","domain_name":"independent","page_name":"davidbruges","display_name":"david bruges","profile_url":"https://independent.academia.edu/davidbruges?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":531,"name":"Organic Chemistry","url":"https://www.academia.edu/Documents/in/Organic_Chemistry?f_ri=1970697","nofollow":true},{"id":10640,"name":"Drug Discovery","url":"https://www.academia.edu/Documents/in/Drug_Discovery?f_ri=1970697","nofollow":true},{"id":12981,"name":"Enzyme Inhibitors","url":"https://www.academia.edu/Documents/in/Enzyme_Inhibitors?f_ri=1970697","nofollow":true},{"id":33441,"name":"Macromolecular X-Ray Crystallography","url":"https://www.academia.edu/Documents/in/Macromolecular_X-Ray_Crystallography?f_ri=1970697","nofollow":true},{"id":55267,"name":"Mitosis","url":"https://www.academia.edu/Documents/in/Mitosis?f_ri=1970697"},{"id":84760,"name":"Mice","url":"https://www.academia.edu/Documents/in/Mice?f_ri=1970697"},{"id":88745,"name":"High throughput screening","url":"https://www.academia.edu/Documents/in/High_throughput_screening?f_ri=1970697"},{"id":168304,"name":"SAR","url":"https://www.academia.edu/Documents/in/SAR?f_ri=1970697"},{"id":315349,"name":"Kinesin","url":"https://www.academia.edu/Documents/in/Kinesin?f_ri=1970697"},{"id":564878,"name":"Body Weight","url":"https://www.academia.edu/Documents/in/Body_Weight?f_ri=1970697"},{"id":728493,"name":"Bioorganic and medicinal Chemistry","url":"https://www.academia.edu/Documents/in/Bioorganic_and_medicinal_Chemistry?f_ri=1970697"},{"id":769359,"name":"Growth Inhibition","url":"https://www.academia.edu/Documents/in/Growth_Inhibition?f_ri=1970697"},{"id":816974,"name":"Quinolines","url":"https://www.academia.edu/Documents/in/Quinolines?f_ri=1970697"},{"id":936268,"name":"Colon Carcinoma","url":"https://www.academia.edu/Documents/in/Colon_Carcinoma?f_ri=1970697"},{"id":967839,"name":"Structure activity Relationship","url":"https://www.academia.edu/Documents/in/Structure_activity_Relationship?f_ri=1970697"},{"id":1212103,"name":"Antineoplastic Agents","url":"https://www.academia.edu/Documents/in/Antineoplastic_Agents?f_ri=1970697"},{"id":1242506,"name":"Binding Site","url":"https://www.academia.edu/Documents/in/Binding_Site?f_ri=1970697"},{"id":1597877,"name":"Nucleotides","url":"https://www.academia.edu/Documents/in/Nucleotides?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_22931348" data-work_id="22931348" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/22931348/Crystallographic_analysis_of_oxygenated_and_deoxygenated_states_of_arthropod_hemocyanin_shows_unusual_differences">Crystallographic analysis of oxygenated and deoxygenated states of arthropod hemocyanin shows unusual differences</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">The X-ray structure of an oxygenated hemocyanin molecule, subunit I1 of Limulus polyphemus hemocyanin, was determined at 2.4 A resolution and refined to a crystallographic R-factor of 17.1%. The 73-kDa subunit crystallizes with the... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_22931348" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">The X-ray structure of an oxygenated hemocyanin molecule, subunit I1 of Limulus polyphemus hemocyanin, was determined at 2.4 A resolution and refined to a crystallographic R-factor of 17.1%. The 73-kDa subunit crystallizes with the symmetry of the space group R32 with one subunit per asymmetric unit forming hexamers with 32 point group symmetry. Molecular oxygen is bound to a dinuclear copper center in the protein's second domain, symmetrically between and equidistant from the two copper atoms. The coppercopper distance in oxygenated Limulus hemocyanin is 3.6 2 0.2 A, which is surprisingly 1 A 0 1994 WILEY-LISS. INC.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/22931348" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="196af0e7a04d46426c2d2930d8c3b36c" rel="nofollow" data-download="{"attachment_id":43461903,"asset_id":22931348,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/43461903/download_file?st=MTc0MDE1NDMyOCw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="32072609" href="https://independent.academia.edu/JosephBonaventura">Joseph Bonaventura</a><script data-card-contents-for-user="32072609" type="text/json">{"id":32072609,"first_name":"Joseph","last_name":"Bonaventura","domain_name":"independent","page_name":"JosephBonaventura","display_name":"Joseph Bonaventura","profile_url":"https://independent.academia.edu/JosephBonaventura?f_ri=1970697","photo":"https://0.academia-photos.com/32072609/9565843/10655807/s65_joseph.bonaventura.jpg_oh_a78c82bfba96688fa0b1f5daf5c9041e_oe_562fdd08___gda___1441962859_f5d22dd73341e1d41860b8df5b7464e3"}</script></span></span></li><li class="js-paper-rank-work_22931348 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="22931348"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 22931348, container: ".js-paper-rank-work_22931348", }); });</script></li><li class="js-percentile-work_22931348 InlineList-item InlineList-item--bordered hidden u-tcGrayDark"><span class="percentile-widget hidden"><span class="u-mr2x percentile-widget" style="display: none">•</span><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 22931348; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-percentile-work_22931348"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></li><li class="js-view-count-work_22931348 InlineList-item InlineList-item--bordered hidden"><div><span><span class="js-view-count view-count u-mr2x" data-work-id="22931348"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 22931348; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=22931348]").text(description); $(".js-view-count-work_22931348").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_22931348").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="22931348"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">12</a>  </div><span class="InlineList-item-text u-textTruncate u-pl10x"><a class="InlineList-item-text" data-has-card-for-ri="8914" rel="nofollow" href="https://www.academia.edu/Documents/in/Protein_Science">Protein Science</a>, <script data-card-contents-for-ri="8914" type="text/json">{"id":8914,"name":"Protein Science","url":"https://www.academia.edu/Documents/in/Protein_Science?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="33441" rel="nofollow" href="https://www.academia.edu/Documents/in/Macromolecular_X-Ray_Crystallography">Macromolecular X-Ray Crystallography</a>, <script data-card-contents-for-ri="33441" type="text/json">{"id":33441,"name":"Macromolecular X-Ray Crystallography","url":"https://www.academia.edu/Documents/in/Macromolecular_X-Ray_Crystallography?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="47884" rel="nofollow" href="https://www.academia.edu/Documents/in/Biological_Sciences">Biological Sciences</a>, <script data-card-contents-for-ri="47884" type="text/json">{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="80414" rel="nofollow" href="https://www.academia.edu/Documents/in/Mathematical_Sciences">Mathematical Sciences</a><script data-card-contents-for-ri="80414" type="text/json">{"id":80414,"name":"Mathematical Sciences","url":"https://www.academia.edu/Documents/in/Mathematical_Sciences?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=22931348]'), work: {"id":22931348,"title":"Crystallographic analysis of oxygenated and deoxygenated states of arthropod hemocyanin shows unusual differences","created_at":"2016-03-07T07:07:00.927-08:00","url":"https://www.academia.edu/22931348/Crystallographic_analysis_of_oxygenated_and_deoxygenated_states_of_arthropod_hemocyanin_shows_unusual_differences?f_ri=1970697","dom_id":"work_22931348","summary":"The X-ray structure of an oxygenated hemocyanin molecule, subunit I1 of Limulus polyphemus hemocyanin, was determined at 2.4 A resolution and refined to a crystallographic R-factor of 17.1%. The 73-kDa subunit crystallizes with the symmetry of the space group R32 with one subunit per asymmetric unit forming hexamers with 32 point group symmetry. Molecular oxygen is bound to a dinuclear copper center in the protein's second domain, symmetrically between and equidistant from the two copper atoms. The coppercopper distance in oxygenated Limulus hemocyanin is 3.6 2 0.2 A, which is surprisingly 1 A 0 1994 WILEY-LISS. INC.","downloadable_attachments":[{"id":43461903,"asset_id":22931348,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":32072609,"first_name":"Joseph","last_name":"Bonaventura","domain_name":"independent","page_name":"JosephBonaventura","display_name":"Joseph Bonaventura","profile_url":"https://independent.academia.edu/JosephBonaventura?f_ri=1970697","photo":"https://0.academia-photos.com/32072609/9565843/10655807/s65_joseph.bonaventura.jpg_oh_a78c82bfba96688fa0b1f5daf5c9041e_oe_562fdd08___gda___1441962859_f5d22dd73341e1d41860b8df5b7464e3"}],"research_interests":[{"id":8914,"name":"Protein Science","url":"https://www.academia.edu/Documents/in/Protein_Science?f_ri=1970697","nofollow":true},{"id":33441,"name":"Macromolecular X-Ray Crystallography","url":"https://www.academia.edu/Documents/in/Macromolecular_X-Ray_Crystallography?f_ri=1970697","nofollow":true},{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true},{"id":80414,"name":"Mathematical Sciences","url":"https://www.academia.edu/Documents/in/Mathematical_Sciences?f_ri=1970697","nofollow":true},{"id":80692,"name":"Copper","url":"https://www.academia.edu/Documents/in/Copper?f_ri=1970697"},{"id":133838,"name":"Horseshoe crabs","url":"https://www.academia.edu/Documents/in/Horseshoe_crabs?f_ri=1970697"},{"id":181569,"name":"Proteins","url":"https://www.academia.edu/Documents/in/Proteins?f_ri=1970697"},{"id":380825,"name":"Oxygen","url":"https://www.academia.edu/Documents/in/Oxygen?f_ri=1970697"},{"id":653665,"name":"Protein Conformation","url":"https://www.academia.edu/Documents/in/Protein_Conformation?f_ri=1970697"},{"id":784076,"name":"Species Specificity","url":"https://www.academia.edu/Documents/in/Species_Specificity?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"},{"id":2295489,"name":"Hemocyanin","url":"https://www.academia.edu/Documents/in/Hemocyanin?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_54101951" data-work_id="54101951" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/54101951/Targeting_Brain_%CE%B17_Nicotinic_Acetylcholine_Receptors_in_Alzheimer_s_Disease_Rationale_and_Current_Status">Targeting Brain α7 Nicotinic Acetylcholine Receptors in Alzheimer’s Disease: Rationale and Current Status</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">Alzheimer's disease (AD) is the most common form of dementia among older persons. Pathognomonic hallmarks of the disease include the development of amyloid senile plaques and deposits of neurofibrillary tangles. These changes occur in the... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_54101951" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">Alzheimer's disease (AD) is the most common form of dementia among older persons. Pathognomonic hallmarks of the disease include the development of amyloid senile plaques and deposits of neurofibrillary tangles. These changes occur in the brain long before the clinical manifestations of AD (cognitive impairment in particular) become apparent. Nicotinic acetylcholine receptors (ACh-Rs), particularly the a7 subtype, are highly expressed in brain regions relevant to cognitive and memory functions and involved in the processing of sensory information. There is strong evidence that implicates the participation of AChRs in AD. This review briefly introduces current strategies addressing the pathophysiologic findings (amyloid-b-peptide plaques, neurofibrillary tangles) and then focuses on more recent efforts of pharmacologic intervention in AD, specifically targeted to the a7 AChR. Whereas cholinesterase inhibitors such as donepezil, galantamine, or rivastigmine, together with the non-competitive N-methyl-D-aspartate receptor antagonist memantine are at the forefront of present-day clinical intervention for AD, new insights into AChR molecular pharmacology are bringing other drugs, directed at AChRs, to center stage. Among these are the positive allosteric modulators that selectively target a7 AChRs and are aimed at unleashing the factors that hinder agonist-mediated, a7 AChR channel activation. This calls for more detailed knowledge of the distribution, functional properties, and involvement of AChRs in various signaling cascades-together with the corresponding abnormalities in all these properties-to be able to engineer strategies in drug design and evaluate the therapeutic possibilities of new compounds targeting this class of neurotransmitter receptors. Key points Alzheimer's disease (AD) is the prevalent form of dementia in older persons. A wealth of evidence supports the notion that the neuronal nicotinic acetylcholine receptor is involved in the pathophysiology of AD. Nicotinic acetylcholine receptors constitute an important pharmacologic target for therapeutic and possibly prophylactic intervention in AD.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/54101951" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="558ede028b028a812fbedd29fed3ea02" rel="nofollow" data-download="{"attachment_id":70629045,"asset_id":54101951,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/70629045/download_file?st=MTc0MDE1NDMyOCw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="132467887" href="https://independent.academia.edu/Vall%C3%A9sSof%C3%ADa">Sofía Vallés</a><script data-card-contents-for-user="132467887" type="text/json">{"id":132467887,"first_name":"Sofía","last_name":"Vallés","domain_name":"independent","page_name":"VallésSofía","display_name":"Sofía Vallés","profile_url":"https://independent.academia.edu/Vall%C3%A9sSof%C3%ADa?f_ri=1970697","photo":"https://0.academia-photos.com/132467887/34632994/30360625/s65_sof_a.vall_s.jpg"}</script></span></span></li><li class="js-paper-rank-work_54101951 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="54101951"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 54101951, container: ".js-paper-rank-work_54101951", }); 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$(".js-view-count[data-work-id=54101951]").text(description); $(".js-view-count-work_54101951").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_54101951").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="54101951"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">8</a>  </div><span class="InlineList-item-text u-textTruncate u-pl9x"><a class="InlineList-item-text" data-has-card-for-ri="4212" rel="nofollow" href="https://www.academia.edu/Documents/in/Cognition">Cognition</a>, <script data-card-contents-for-ri="4212" type="text/json">{"id":4212,"name":"Cognition","url":"https://www.academia.edu/Documents/in/Cognition?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="208138" rel="nofollow" href="https://www.academia.edu/Documents/in/Cholinesterase_inhibitors">Cholinesterase inhibitors</a>, <script data-card-contents-for-ri="208138" type="text/json">{"id":208138,"name":"Cholinesterase inhibitors","url":"https://www.academia.edu/Documents/in/Cholinesterase_inhibitors?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="727044" rel="nofollow" href="https://www.academia.edu/Documents/in/CNS_drugs">CNS drugs</a>, <script data-card-contents-for-ri="727044" type="text/json">{"id":727044,"name":"CNS drugs","url":"https://www.academia.edu/Documents/in/CNS_drugs?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="992249" rel="nofollow" href="https://www.academia.edu/Documents/in/Neurofibrillary_Tangles">Neurofibrillary Tangles</a><script data-card-contents-for-ri="992249" type="text/json">{"id":992249,"name":"Neurofibrillary Tangles","url":"https://www.academia.edu/Documents/in/Neurofibrillary_Tangles?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=54101951]'), work: {"id":54101951,"title":"Targeting Brain α7 Nicotinic Acetylcholine Receptors in Alzheimer’s Disease: Rationale and Current Status","created_at":"2021-09-29T19:49:56.359-07:00","url":"https://www.academia.edu/54101951/Targeting_Brain_%CE%B17_Nicotinic_Acetylcholine_Receptors_in_Alzheimer_s_Disease_Rationale_and_Current_Status?f_ri=1970697","dom_id":"work_54101951","summary":"Alzheimer's disease (AD) is the most common form of dementia among older persons. Pathognomonic hallmarks of the disease include the development of amyloid senile plaques and deposits of neurofibrillary tangles. These changes occur in the brain long before the clinical manifestations of AD (cognitive impairment in particular) become apparent. Nicotinic acetylcholine receptors (ACh-Rs), particularly the a7 subtype, are highly expressed in brain regions relevant to cognitive and memory functions and involved in the processing of sensory information. There is strong evidence that implicates the participation of AChRs in AD. This review briefly introduces current strategies addressing the pathophysiologic findings (amyloid-b-peptide plaques, neurofibrillary tangles) and then focuses on more recent efforts of pharmacologic intervention in AD, specifically targeted to the a7 AChR. Whereas cholinesterase inhibitors such as donepezil, galantamine, or rivastigmine, together with the non-competitive N-methyl-D-aspartate receptor antagonist memantine are at the forefront of present-day clinical intervention for AD, new insights into AChR molecular pharmacology are bringing other drugs, directed at AChRs, to center stage. Among these are the positive allosteric modulators that selectively target a7 AChRs and are aimed at unleashing the factors that hinder agonist-mediated, a7 AChR channel activation. This calls for more detailed knowledge of the distribution, functional properties, and involvement of AChRs in various signaling cascades-together with the corresponding abnormalities in all these properties-to be able to engineer strategies in drug design and evaluate the therapeutic possibilities of new compounds targeting this class of neurotransmitter receptors. Key points Alzheimer's disease (AD) is the prevalent form of dementia in older persons. A wealth of evidence supports the notion that the neuronal nicotinic acetylcholine receptor is involved in the pathophysiology of AD. Nicotinic acetylcholine receptors constitute an important pharmacologic target for therapeutic and possibly prophylactic intervention in AD.","downloadable_attachments":[{"id":70629045,"asset_id":54101951,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":132467887,"first_name":"Sofía","last_name":"Vallés","domain_name":"independent","page_name":"VallésSofía","display_name":"Sofía Vallés","profile_url":"https://independent.academia.edu/Vall%C3%A9sSof%C3%ADa?f_ri=1970697","photo":"https://0.academia-photos.com/132467887/34632994/30360625/s65_sof_a.vall_s.jpg"}],"research_interests":[{"id":4212,"name":"Cognition","url":"https://www.academia.edu/Documents/in/Cognition?f_ri=1970697","nofollow":true},{"id":208138,"name":"Cholinesterase inhibitors","url":"https://www.academia.edu/Documents/in/Cholinesterase_inhibitors?f_ri=1970697","nofollow":true},{"id":727044,"name":"CNS drugs","url":"https://www.academia.edu/Documents/in/CNS_drugs?f_ri=1970697","nofollow":true},{"id":992249,"name":"Neurofibrillary Tangles","url":"https://www.academia.edu/Documents/in/Neurofibrillary_Tangles?f_ri=1970697","nofollow":true},{"id":1120234,"name":"Alzheimer Disease","url":"https://www.academia.edu/Documents/in/Alzheimer_Disease?f_ri=1970697"},{"id":1239755,"name":"Neurosciences","url":"https://www.academia.edu/Documents/in/Neurosciences?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"},{"id":3789884,"name":"Pharmacology and pharmaceutical sciences","url":"https://www.academia.edu/Documents/in/Pharmacology_and_pharmaceutical_sciences?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_14706373" data-work_id="14706373" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/14706373/Molecular_and_functional_characterization_of_hemocyanin_of_the_giant_African_millipede_Archispirostreptus_gigas">Molecular and functional characterization of hemocyanin of the giant African millipede, Archispirostreptus gigas</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">In contrast to other terrestrial arthropods, where gaseous O 2 that fuels aerobic metabolism diffuses to the tissues in tracheal tubes, and most other metazoans, where O 2 is transported to tissues by circulating respiratory proteins, the... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_14706373" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">In contrast to other terrestrial arthropods, where gaseous O 2 that fuels aerobic metabolism diffuses to the tissues in tracheal tubes, and most other metazoans, where O 2 is transported to tissues by circulating respiratory proteins, the myriapods (millipedes and centipedes) strikingly have tracheal systems as well as circulating hemocyanin (Hc). In order to elucidate the evolutionary origin and biological significance of millipede Hc, we report the molecular structure (subunit composition and amino acid sequence) of multimeric (36-mer) Hc from the forest floor-dwelling giant African millipede Archispirostreptus gigas and its allosteric oxygen-binding properties under various physico-chemical conditions. Archispirostreptus gigas Hc consists of only a single subunit type with differential glycosylation. Phylogenic analysis revealed that millipede Hc is a sister group to centipede HcA, which supports an early divergence of distinct Hc subunits in myriapods and an ancient origin of multimeric Hcs.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/14706373" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="6e158e636e324c243abe5b542241a8c2" rel="nofollow" data-download="{"attachment_id":43957615,"asset_id":14706373,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/43957615/download_file?st=MTc0MDE1NDMyOCw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="33660448" href="https://au.academia.edu/AngelaFago">Angela Fago</a><script data-card-contents-for-user="33660448" type="text/json">{"id":33660448,"first_name":"Angela","last_name":"Fago","domain_name":"au","page_name":"AngelaFago","display_name":"Angela Fago","profile_url":"https://au.academia.edu/AngelaFago?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_14706373 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="14706373"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 14706373, container: ".js-paper-rank-work_14706373", }); 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$(".js-view-count[data-work-id=14706373]").text(description); $(".js-view-count-work_14706373").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_14706373").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="14706373"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">17</a>  </div><span class="InlineList-item-text u-textTruncate u-pl10x"><a class="InlineList-item-text" data-has-card-for-ri="2513" rel="nofollow" href="https://www.academia.edu/Documents/in/Molecular_Biology">Molecular Biology</a>, <script data-card-contents-for-ri="2513" type="text/json">{"id":2513,"name":"Molecular Biology","url":"https://www.academia.edu/Documents/in/Molecular_Biology?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="3284" rel="nofollow" href="https://www.academia.edu/Documents/in/Bacteriology">Bacteriology</a>, <script data-card-contents-for-ri="3284" type="text/json">{"id":3284,"name":"Bacteriology","url":"https://www.academia.edu/Documents/in/Bacteriology?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="4527" rel="nofollow" href="https://www.academia.edu/Documents/in/Africa">Africa</a>, <script data-card-contents-for-ri="4527" type="text/json">{"id":4527,"name":"Africa","url":"https://www.academia.edu/Documents/in/Africa?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="9534" rel="nofollow" href="https://www.academia.edu/Documents/in/Calcium">Calcium</a><script data-card-contents-for-ri="9534" type="text/json">{"id":9534,"name":"Calcium","url":"https://www.academia.edu/Documents/in/Calcium?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=14706373]'), work: {"id":14706373,"title":"Molecular and functional characterization of hemocyanin of the giant African millipede, Archispirostreptus gigas","created_at":"2015-08-05T23:24:58.364-07:00","url":"https://www.academia.edu/14706373/Molecular_and_functional_characterization_of_hemocyanin_of_the_giant_African_millipede_Archispirostreptus_gigas?f_ri=1970697","dom_id":"work_14706373","summary":"In contrast to other terrestrial arthropods, where gaseous O 2 that fuels aerobic metabolism diffuses to the tissues in tracheal tubes, and most other metazoans, where O 2 is transported to tissues by circulating respiratory proteins, the myriapods (millipedes and centipedes) strikingly have tracheal systems as well as circulating hemocyanin (Hc). In order to elucidate the evolutionary origin and biological significance of millipede Hc, we report the molecular structure (subunit composition and amino acid sequence) of multimeric (36-mer) Hc from the forest floor-dwelling giant African millipede Archispirostreptus gigas and its allosteric oxygen-binding properties under various physico-chemical conditions. Archispirostreptus gigas Hc consists of only a single subunit type with differential glycosylation. Phylogenic analysis revealed that millipede Hc is a sister group to centipede HcA, which supports an early divergence of distinct Hc subunits in myriapods and an ancient origin of multimeric Hcs.","downloadable_attachments":[{"id":43957615,"asset_id":14706373,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":33660448,"first_name":"Angela","last_name":"Fago","domain_name":"au","page_name":"AngelaFago","display_name":"Angela Fago","profile_url":"https://au.academia.edu/AngelaFago?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":2513,"name":"Molecular Biology","url":"https://www.academia.edu/Documents/in/Molecular_Biology?f_ri=1970697","nofollow":true},{"id":3284,"name":"Bacteriology","url":"https://www.academia.edu/Documents/in/Bacteriology?f_ri=1970697","nofollow":true},{"id":4527,"name":"Africa","url":"https://www.academia.edu/Documents/in/Africa?f_ri=1970697","nofollow":true},{"id":9534,"name":"Calcium","url":"https://www.academia.edu/Documents/in/Calcium?f_ri=1970697","nofollow":true},{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697"},{"id":54433,"name":"Phylogeny","url":"https://www.academia.edu/Documents/in/Phylogeny?f_ri=1970697"},{"id":164264,"name":"Body Size","url":"https://www.academia.edu/Documents/in/Body_Size?f_ri=1970697"},{"id":193464,"name":"Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis","url":"https://www.academia.edu/Documents/in/Sodium_Dodecyl_Sulfate-Polyacrylamide_Gel_Electrophoresis?f_ri=1970697"},{"id":245668,"name":"Arthropods","url":"https://www.academia.edu/Documents/in/Arthropods?f_ri=1970697"},{"id":380825,"name":"Oxygen","url":"https://www.academia.edu/Documents/in/Oxygen?f_ri=1970697"},{"id":880279,"name":"Bayes Theorem","url":"https://www.academia.edu/Documents/in/Bayes_Theorem-1?f_ri=1970697"},{"id":1010725,"name":"Protein Binding","url":"https://www.academia.edu/Documents/in/Protein_Binding?f_ri=1970697"},{"id":1137254,"name":"Hydrogen-Ion Concentration","url":"https://www.academia.edu/Documents/in/Hydrogen-Ion_Concentration?f_ri=1970697"},{"id":1681026,"name":"Biochemistry and cell biology","url":"https://www.academia.edu/Documents/in/Biochemistry_and_cell_biology?f_ri=1970697"},{"id":1764230,"name":"Experimental Biology","url":"https://www.academia.edu/Documents/in/Experimental_Biology?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"},{"id":2295489,"name":"Hemocyanin","url":"https://www.academia.edu/Documents/in/Hemocyanin?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_21230682" data-work_id="21230682" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/21230682/The_lactose_repressor_system_paradigms_for_regulation_allosteric_behavior_and_protein_folding">The lactose repressor system: paradigms for regulation, allosteric behavior and protein folding</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">In 1961, Jacob and Monod proposed the operon model for gene regulation based on metabolism of lactose in Escherichia coli [1]. This proposal was followed by an explication of allosteric behavior by Monod and colleagues [2]. The operon... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_21230682" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">In 1961, Jacob and Monod proposed the operon model for gene regulation based on metabolism of lactose in Escherichia coli [1]. This proposal was followed by an explication of allosteric behavior by Monod and colleagues [2]. The operon model rationally depicted how genetic mechanisms can control metabolic events in response to environmental stimuli via coordinated transcription of a set of genes with related function (e.g. metabolism of lactose). The allosteric response found in the lactose repressor and many other proteins has been extended to a variety of cellular signaling pathways in all organisms. These two models have shaped our view of modern molecular biology and captivated the attention of a surprisingly broad range of scientists. More recently, the lactose repressor monomer was used as a model system for experimental and theoretical explorations of protein folding mechanisms. Thus, the lac system continues to advance our molecular understanding of genetic control and the relationship between sequence, structure and function.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/21230682" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="44d53711987965cef8d06c57b95501ef" rel="nofollow" data-download="{"attachment_id":41773403,"asset_id":21230682,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/41773403/download_file?st=MTc0MDE1NDMyOCw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="42367835" href="https://independent.academia.edu/HongliZhan">Hongli Zhan</a><script data-card-contents-for-user="42367835" type="text/json">{"id":42367835,"first_name":"Hongli","last_name":"Zhan","domain_name":"independent","page_name":"HongliZhan","display_name":"Hongli Zhan","profile_url":"https://independent.academia.edu/HongliZhan?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_21230682 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="21230682"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 21230682, container: ".js-paper-rank-work_21230682", }); });</script></li><li class="js-percentile-work_21230682 InlineList-item InlineList-item--bordered hidden u-tcGrayDark"><span class="percentile-widget hidden"><span class="u-mr2x percentile-widget" style="display: none">•</span><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 21230682; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-percentile-work_21230682"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></li><li class="js-view-count-work_21230682 InlineList-item InlineList-item--bordered hidden"><div><span><span class="js-view-count view-count u-mr2x" data-work-id="21230682"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 21230682; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=21230682]").text(description); $(".js-view-count-work_21230682").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_21230682").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="21230682"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">17</a>  </div><span class="InlineList-item-text u-textTruncate u-pl10x"><a class="InlineList-item-text" data-has-card-for-ri="156" rel="nofollow" href="https://www.academia.edu/Documents/in/Genetics">Genetics</a>, <script data-card-contents-for-ri="156" type="text/json">{"id":156,"name":"Genetics","url":"https://www.academia.edu/Documents/in/Genetics?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="167" rel="nofollow" href="https://www.academia.edu/Documents/in/Physiology">Physiology</a>, <script data-card-contents-for-ri="167" type="text/json">{"id":167,"name":"Physiology","url":"https://www.academia.edu/Documents/in/Physiology?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="2513" rel="nofollow" href="https://www.academia.edu/Documents/in/Molecular_Biology">Molecular Biology</a>, <script data-card-contents-for-ri="2513" type="text/json">{"id":2513,"name":"Molecular Biology","url":"https://www.academia.edu/Documents/in/Molecular_Biology?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="3971" rel="nofollow" href="https://www.academia.edu/Documents/in/Protein_Folding">Protein Folding</a><script data-card-contents-for-ri="3971" type="text/json">{"id":3971,"name":"Protein Folding","url":"https://www.academia.edu/Documents/in/Protein_Folding?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=21230682]'), work: {"id":21230682,"title":"The lactose repressor system: paradigms for regulation, allosteric behavior and protein folding","created_at":"2016-01-30T05:03:58.150-08:00","url":"https://www.academia.edu/21230682/The_lactose_repressor_system_paradigms_for_regulation_allosteric_behavior_and_protein_folding?f_ri=1970697","dom_id":"work_21230682","summary":"In 1961, Jacob and Monod proposed the operon model for gene regulation based on metabolism of lactose in Escherichia coli [1]. This proposal was followed by an explication of allosteric behavior by Monod and colleagues [2]. The operon model rationally depicted how genetic mechanisms can control metabolic events in response to environmental stimuli via coordinated transcription of a set of genes with related function (e.g. metabolism of lactose). The allosteric response found in the lactose repressor and many other proteins has been extended to a variety of cellular signaling pathways in all organisms. These two models have shaped our view of modern molecular biology and captivated the attention of a surprisingly broad range of scientists. More recently, the lactose repressor monomer was used as a model system for experimental and theoretical explorations of protein folding mechanisms. Thus, the lac system continues to advance our molecular understanding of genetic control and the relationship between sequence, structure and function.","downloadable_attachments":[{"id":41773403,"asset_id":21230682,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":42367835,"first_name":"Hongli","last_name":"Zhan","domain_name":"independent","page_name":"HongliZhan","display_name":"Hongli Zhan","profile_url":"https://independent.academia.edu/HongliZhan?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":156,"name":"Genetics","url":"https://www.academia.edu/Documents/in/Genetics?f_ri=1970697","nofollow":true},{"id":167,"name":"Physiology","url":"https://www.academia.edu/Documents/in/Physiology?f_ri=1970697","nofollow":true},{"id":2513,"name":"Molecular Biology","url":"https://www.academia.edu/Documents/in/Molecular_Biology?f_ri=1970697","nofollow":true},{"id":3971,"name":"Protein Folding","url":"https://www.academia.edu/Documents/in/Protein_Folding?f_ri=1970697","nofollow":true},{"id":4338,"name":"Gene regulation","url":"https://www.academia.edu/Documents/in/Gene_regulation?f_ri=1970697"},{"id":10937,"name":"Transcription Regulation","url":"https://www.academia.edu/Documents/in/Transcription_Regulation?f_ri=1970697"},{"id":49646,"name":"Protein Structure and Function","url":"https://www.academia.edu/Documents/in/Protein_Structure_and_Function?f_ri=1970697"},{"id":69542,"name":"Computer Simulation","url":"https://www.academia.edu/Documents/in/Computer_Simulation?f_ri=1970697"},{"id":74780,"name":"Mutation","url":"https://www.academia.edu/Documents/in/Mutation?f_ri=1970697"},{"id":83128,"name":"Escherichia coli","url":"https://www.academia.edu/Documents/in/Escherichia_coli?f_ri=1970697"},{"id":144129,"name":"Allostery","url":"https://www.academia.edu/Documents/in/Allostery?f_ri=1970697"},{"id":244814,"name":"Clinical Sciences","url":"https://www.academia.edu/Documents/in/Clinical_Sciences?f_ri=1970697"},{"id":302688,"name":"Operator","url":"https://www.academia.edu/Documents/in/Operator?f_ri=1970697"},{"id":434746,"name":"Model System","url":"https://www.academia.edu/Documents/in/Model_System?f_ri=1970697"},{"id":653665,"name":"Protein Conformation","url":"https://www.academia.edu/Documents/in/Protein_Conformation?f_ri=1970697"},{"id":1681026,"name":"Biochemistry and cell biology","url":"https://www.academia.edu/Documents/in/Biochemistry_and_cell_biology?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_33284212" data-work_id="33284212" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/33284212/The_power_of_two_protein_dimerization_in_biology">The power of two: protein dimerization in biology</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">The self-association of proteins to form dimers and higher-order oligomers is a very common phenomenon. Recent structural and biophysical studies show that protein dimerization or oligomerization is a key factor in the regulation of... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_33284212" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">The self-association of proteins to form dimers and higher-order oligomers is a very common phenomenon. Recent structural and biophysical studies show that protein dimerization or oligomerization is a key factor in the regulation of proteins such as enzymes, ion channels, receptors and transcription factors. In addition, self-association can help to minimize genome size, while maintaining the advantages of modular complex formation. Oligomerization, however, can also have deleterious consequences when nonnative oligomers associated with pathogenic states are generated. Specific protein dimerization is integral to biological function, structure and control, and must be under substantial selection pressure to be maintained with such frequency throughout biology.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/33284212" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="3da3423dea80db7b101d40ab18c0e908" rel="nofollow" data-download="{"attachment_id":53351134,"asset_id":33284212,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/53351134/download_file?st=MTc0MDE1NDMyOCw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="65007315" href="https://independent.academia.edu/MargaretSunde">Margaret Sunde</a><script data-card-contents-for-user="65007315" type="text/json">{"id":65007315,"first_name":"Margaret","last_name":"Sunde","domain_name":"independent","page_name":"MargaretSunde","display_name":"Margaret Sunde","profile_url":"https://independent.academia.edu/MargaretSunde?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_33284212 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="33284212"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 33284212, container: ".js-paper-rank-work_33284212", }); });</script></li><li class="js-percentile-work_33284212 InlineList-item InlineList-item--bordered hidden u-tcGrayDark"><span class="percentile-widget hidden"><span class="u-mr2x percentile-widget" style="display: none">•</span><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 33284212; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-percentile-work_33284212"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></li><li class="js-view-count-work_33284212 InlineList-item InlineList-item--bordered hidden"><div><span><span class="js-view-count view-count u-mr2x" data-work-id="33284212"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 33284212; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=33284212]").text(description); $(".js-view-count-work_33284212").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_33284212").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="33284212"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">11</a>  </div><span class="InlineList-item-text u-textTruncate u-pl10x"><a class="InlineList-item-text" data-has-card-for-ri="40539" rel="nofollow" href="https://www.academia.edu/Documents/in/Amyloid">Amyloid</a>, <script data-card-contents-for-ri="40539" type="text/json">{"id":40539,"name":"Amyloid","url":"https://www.academia.edu/Documents/in/Amyloid?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="47884" rel="nofollow" href="https://www.academia.edu/Documents/in/Biological_Sciences">Biological Sciences</a>, <script data-card-contents-for-ri="47884" type="text/json">{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="181569" rel="nofollow" href="https://www.academia.edu/Documents/in/Proteins">Proteins</a>, <script data-card-contents-for-ri="181569" type="text/json">{"id":181569,"name":"Proteins","url":"https://www.academia.edu/Documents/in/Proteins?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="260118" rel="nofollow" href="https://www.academia.edu/Documents/in/CHEMICAL_SCIENCES">CHEMICAL SCIENCES</a><script data-card-contents-for-ri="260118" type="text/json">{"id":260118,"name":"CHEMICAL SCIENCES","url":"https://www.academia.edu/Documents/in/CHEMICAL_SCIENCES?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=33284212]'), work: {"id":33284212,"title":"The power of two: protein dimerization in biology","created_at":"2017-05-31T21:54:59.928-07:00","url":"https://www.academia.edu/33284212/The_power_of_two_protein_dimerization_in_biology?f_ri=1970697","dom_id":"work_33284212","summary":"The self-association of proteins to form dimers and higher-order oligomers is a very common phenomenon. Recent structural and biophysical studies show that protein dimerization or oligomerization is a key factor in the regulation of proteins such as enzymes, ion channels, receptors and transcription factors. In addition, self-association can help to minimize genome size, while maintaining the advantages of modular complex formation. Oligomerization, however, can also have deleterious consequences when nonnative oligomers associated with pathogenic states are generated. Specific protein dimerization is integral to biological function, structure and control, and must be under substantial selection pressure to be maintained with such frequency throughout biology.","downloadable_attachments":[{"id":53351134,"asset_id":33284212,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":65007315,"first_name":"Margaret","last_name":"Sunde","domain_name":"independent","page_name":"MargaretSunde","display_name":"Margaret Sunde","profile_url":"https://independent.academia.edu/MargaretSunde?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":40539,"name":"Amyloid","url":"https://www.academia.edu/Documents/in/Amyloid?f_ri=1970697","nofollow":true},{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true},{"id":181569,"name":"Proteins","url":"https://www.academia.edu/Documents/in/Proteins?f_ri=1970697","nofollow":true},{"id":260118,"name":"CHEMICAL SCIENCES","url":"https://www.academia.edu/Documents/in/CHEMICAL_SCIENCES?f_ri=1970697","nofollow":true},{"id":956752,"name":"Protein Quaternary Structure","url":"https://www.academia.edu/Documents/in/Protein_Quaternary_Structure?f_ri=1970697"},{"id":1186610,"name":"DNA binding proteins","url":"https://www.academia.edu/Documents/in/DNA_binding_proteins?f_ri=1970697"},{"id":1457054,"name":"Protein Transport","url":"https://www.academia.edu/Documents/in/Protein_Transport?f_ri=1970697"},{"id":1763968,"name":"Gene Expression Regulation","url":"https://www.academia.edu/Documents/in/Gene_Expression_Regulation?f_ri=1970697"},{"id":1809037,"name":"Dimerization","url":"https://www.academia.edu/Documents/in/Dimerization?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"},{"id":2468093,"name":"Cell Membrane","url":"https://www.academia.edu/Documents/in/Cell_Membrane?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_7432205" data-work_id="7432205" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/7432205/Inhibition_of_tumor_angiogenesis_and_growth_by_a_small_molecule_multi_FGF_receptor_blocker_with_allosteric_properties">Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">Receptor tyrosine kinases (RTK) are targets for anticancer drug development. To date, only RTK inhibitors that block orthosteric binding of ligands and substrates have been developed. Here, we report the pharmacologic characterization of... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_7432205" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">Receptor tyrosine kinases (RTK) are targets for anticancer drug development. To date, only RTK inhibitors that block orthosteric binding of ligands and substrates have been developed. Here, we report the pharmacologic characterization of the chemical SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling by binding to the extracellular FGFR domain without affecting orthosteric FGF binding. SSR exhibits allosteric properties, including probe dependence, signaling bias, and ceiling effects. Inhibition by SSR is highly conserved throughout the animal kingdom. Oral delivery of SSR inhibits arthritis and tumors that are relatively refractory to anti-vascular endothelial growth factor receptor-2 antibodies. Thus, orally active, extracellularly acting small-molecule modulators of RTKs with allosteric properties can be developed and may offer opportunities to improve anticancer treatment.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/7432205" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="d1fbf4401b639476f6c7a7bc15677017" rel="nofollow" data-download="{"attachment_id":48476636,"asset_id":7432205,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/48476636/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="1567427" href="https://gakushuin.academia.edu/ToruShimada">Toru Shimada</a><script data-card-contents-for-user="1567427" type="text/json">{"id":1567427,"first_name":"Toru","last_name":"Shimada","domain_name":"gakushuin","page_name":"ToruShimada","display_name":"Toru Shimada","profile_url":"https://gakushuin.academia.edu/ToruShimada?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_7432205 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="7432205"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 7432205, container: ".js-paper-rank-work_7432205", }); });</script></li><li class="js-percentile-work_7432205 InlineList-item InlineList-item--bordered hidden u-tcGrayDark"><span class="percentile-widget hidden"><span class="u-mr2x percentile-widget" style="display: none">•</span><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 7432205; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-percentile-work_7432205"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></li><li class="js-view-count-work_7432205 InlineList-item InlineList-item--bordered hidden"><div><span><span class="js-view-count view-count u-mr2x" data-work-id="7432205"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 7432205; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=7432205]").text(description); $(".js-view-count-work_7432205").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_7432205").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="7432205"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">14</a>  </div><span class="InlineList-item-text u-textTruncate u-pl10x"><a class="InlineList-item-text" data-has-card-for-ri="38831" rel="nofollow" href="https://www.academia.edu/Documents/in/Signal_Transduction">Signal Transduction</a>, <script data-card-contents-for-ri="38831" type="text/json">{"id":38831,"name":"Signal Transduction","url":"https://www.academia.edu/Documents/in/Signal_Transduction?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="51789" rel="nofollow" href="https://www.academia.edu/Documents/in/Antibodies">Antibodies</a>, <script data-card-contents-for-ri="51789" type="text/json">{"id":51789,"name":"Antibodies","url":"https://www.academia.edu/Documents/in/Antibodies?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="84760" rel="nofollow" href="https://www.academia.edu/Documents/in/Mice">Mice</a>, <script data-card-contents-for-ri="84760" type="text/json">{"id":84760,"name":"Mice","url":"https://www.academia.edu/Documents/in/Mice?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="147196" rel="nofollow" href="https://www.academia.edu/Documents/in/Monoclonal_Antibodies">Monoclonal Antibodies</a><script data-card-contents-for-ri="147196" type="text/json">{"id":147196,"name":"Monoclonal Antibodies","url":"https://www.academia.edu/Documents/in/Monoclonal_Antibodies?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=7432205]'), work: {"id":7432205,"title":"Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties","created_at":"2014-06-23T02:28:03.490-07:00","url":"https://www.academia.edu/7432205/Inhibition_of_tumor_angiogenesis_and_growth_by_a_small_molecule_multi_FGF_receptor_blocker_with_allosteric_properties?f_ri=1970697","dom_id":"work_7432205","summary":"Receptor tyrosine kinases (RTK) are targets for anticancer drug development. To date, only RTK inhibitors that block orthosteric binding of ligands and substrates have been developed. Here, we report the pharmacologic characterization of the chemical SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling by binding to the extracellular FGFR domain without affecting orthosteric FGF binding. SSR exhibits allosteric properties, including probe dependence, signaling bias, and ceiling effects. Inhibition by SSR is highly conserved throughout the animal kingdom. Oral delivery of SSR inhibits arthritis and tumors that are relatively refractory to anti-vascular endothelial growth factor receptor-2 antibodies. Thus, orally active, extracellularly acting small-molecule modulators of RTKs with allosteric properties can be developed and may offer opportunities to improve anticancer treatment.","downloadable_attachments":[{"id":48476636,"asset_id":7432205,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":1567427,"first_name":"Toru","last_name":"Shimada","domain_name":"gakushuin","page_name":"ToruShimada","display_name":"Toru Shimada","profile_url":"https://gakushuin.academia.edu/ToruShimada?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":38831,"name":"Signal Transduction","url":"https://www.academia.edu/Documents/in/Signal_Transduction?f_ri=1970697","nofollow":true},{"id":51789,"name":"Antibodies","url":"https://www.academia.edu/Documents/in/Antibodies?f_ri=1970697","nofollow":true},{"id":84760,"name":"Mice","url":"https://www.academia.edu/Documents/in/Mice?f_ri=1970697","nofollow":true},{"id":147196,"name":"Monoclonal Antibodies","url":"https://www.academia.edu/Documents/in/Monoclonal_Antibodies?f_ri=1970697","nofollow":true},{"id":172083,"name":"Phosphorylation","url":"https://www.academia.edu/Documents/in/Phosphorylation?f_ri=1970697"},{"id":197296,"name":"Fibroblast Growth Factor","url":"https://www.academia.edu/Documents/in/Fibroblast_Growth_Factor?f_ri=1970697"},{"id":329844,"name":"Experimental","url":"https://www.academia.edu/Documents/in/Experimental?f_ri=1970697"},{"id":432360,"name":"Receptors","url":"https://www.academia.edu/Documents/in/Receptors?f_ri=1970697"},{"id":506082,"name":"Cancer Cell","url":"https://www.academia.edu/Documents/in/Cancer_Cell?f_ri=1970697"},{"id":1239755,"name":"Neurosciences","url":"https://www.academia.edu/Documents/in/Neurosciences?f_ri=1970697"},{"id":1343089,"name":"Protein Kinase Inhibitors","url":"https://www.academia.edu/Documents/in/Protein_Kinase_Inhibitors?f_ri=1970697"},{"id":1399820,"name":"Bone Resorption","url":"https://www.academia.edu/Documents/in/Bone_Resorption?f_ri=1970697"},{"id":1686435,"name":"Monoclonal","url":"https://www.academia.edu/Documents/in/Monoclonal?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_14481210" data-work_id="14481210" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/14481210/Spd2_assists_Spd1_in_modulation_of_RNR_architecture_but_does_not_regulate_deoxynucleotide_pools">Spd2 assists Spd1 in modulation of RNR architecture but does not regulate deoxynucleotide pools</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">In yeasts, small intrinsically disordered proteins (IDPs) modulate ribonucleotide reductase (RNR) activity to ensure an optimal supply of dNTPs for DNA synthesis. The Schizosaccharomyces pombe Spd1 protein can directly inhibit the large... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_14481210" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">In yeasts, small intrinsically disordered proteins (IDPs) modulate ribonucleotide reductase (RNR) activity to ensure an optimal supply of dNTPs for DNA synthesis. The Schizosaccharomyces pombe Spd1 protein can directly inhibit the large RNR subunit (R1), import the small subunit (R2) into the nucleus and induce an architectural change in the R1-R2 holocomplex. Here, we report the characterization of Spd2, a protein with sequence similarity to Spd1. We show that Spd2 is a CRL4 Cdt2 -controlled IDP that functions together with Spd1 in the DNA damage response and in modulation of RNR architecture. However, Spd2 does not regulate dNTP pools and R2 nuclear import. Furthermore, deletion of spd2 only weakly suppresses the Rad3 ATR checkpoint dependency of CRL4 Cdt2 mutants. However, when we raised intracellular dNTP pools by inactivation of RNR feedback inhibition, deletion of spd2 could suppress the checkpoint dependency of CRL4 Cdt2 mutant cells to the same extent as deletion of spd1. Collectively, these observations suggest that Spd1 on its own regulates dNTP pools, whereas in combination with Spd2 it modulates RNR architecture and sensitizes cells to DNA damage.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/14481210" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="8025d0f088960e5eb51b275aae5c960c" rel="nofollow" data-download="{"attachment_id":44120780,"asset_id":14481210,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/44120780/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="33425126" href="https://independent.academia.edu/AntonyCarr">Antony Carr</a><script data-card-contents-for-user="33425126" type="text/json">{"id":33425126,"first_name":"Antony","last_name":"Carr","domain_name":"independent","page_name":"AntonyCarr","display_name":"Antony Carr","profile_url":"https://independent.academia.edu/AntonyCarr?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_14481210 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="14481210"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 14481210, container: ".js-paper-rank-work_14481210", }); });</script></li><li class="js-percentile-work_14481210 InlineList-item InlineList-item--bordered hidden u-tcGrayDark"><span class="percentile-widget hidden"><span class="u-mr2x percentile-widget" style="display: none">•</span><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 14481210; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-percentile-work_14481210"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></li><li class="js-view-count-work_14481210 InlineList-item InlineList-item--bordered hidden"><div><span><span class="js-view-count view-count u-mr2x" data-work-id="14481210"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 14481210; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=14481210]").text(description); $(".js-view-count-work_14481210").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_14481210").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="14481210"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">12</a>  </div><span class="InlineList-item-text u-textTruncate u-pl10x"><a class="InlineList-item-text" data-has-card-for-ri="9113" rel="nofollow" href="https://www.academia.edu/Documents/in/Cell_Cycle">Cell Cycle</a>, <script data-card-contents-for-ri="9113" type="text/json">{"id":9113,"name":"Cell Cycle","url":"https://www.academia.edu/Documents/in/Cell_Cycle?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="23067" rel="nofollow" href="https://www.academia.edu/Documents/in/DNA_repair">DNA repair</a>, <script data-card-contents-for-ri="23067" type="text/json">{"id":23067,"name":"DNA repair","url":"https://www.academia.edu/Documents/in/DNA_repair?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="47884" rel="nofollow" href="https://www.academia.edu/Documents/in/Biological_Sciences">Biological Sciences</a>, <script data-card-contents-for-ri="47884" type="text/json">{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="74780" rel="nofollow" href="https://www.academia.edu/Documents/in/Mutation">Mutation</a><script data-card-contents-for-ri="74780" type="text/json">{"id":74780,"name":"Mutation","url":"https://www.academia.edu/Documents/in/Mutation?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=14481210]'), work: {"id":14481210,"title":"Spd2 assists Spd1 in modulation of RNR architecture but does not regulate deoxynucleotide pools","created_at":"2015-07-29T01:18:38.129-07:00","url":"https://www.academia.edu/14481210/Spd2_assists_Spd1_in_modulation_of_RNR_architecture_but_does_not_regulate_deoxynucleotide_pools?f_ri=1970697","dom_id":"work_14481210","summary":"In yeasts, small intrinsically disordered proteins (IDPs) modulate ribonucleotide reductase (RNR) activity to ensure an optimal supply of dNTPs for DNA synthesis. The Schizosaccharomyces pombe Spd1 protein can directly inhibit the large RNR subunit (R1), import the small subunit (R2) into the nucleus and induce an architectural change in the R1-R2 holocomplex. Here, we report the characterization of Spd2, a protein with sequence similarity to Spd1. We show that Spd2 is a CRL4 Cdt2 -controlled IDP that functions together with Spd1 in the DNA damage response and in modulation of RNR architecture. However, Spd2 does not regulate dNTP pools and R2 nuclear import. Furthermore, deletion of spd2 only weakly suppresses the Rad3 ATR checkpoint dependency of CRL4 Cdt2 mutants. However, when we raised intracellular dNTP pools by inactivation of RNR feedback inhibition, deletion of spd2 could suppress the checkpoint dependency of CRL4 Cdt2 mutant cells to the same extent as deletion of spd1. Collectively, these observations suggest that Spd1 on its own regulates dNTP pools, whereas in combination with Spd2 it modulates RNR architecture and sensitizes cells to DNA damage.","downloadable_attachments":[{"id":44120780,"asset_id":14481210,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":33425126,"first_name":"Antony","last_name":"Carr","domain_name":"independent","page_name":"AntonyCarr","display_name":"Antony Carr","profile_url":"https://independent.academia.edu/AntonyCarr?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":9113,"name":"Cell Cycle","url":"https://www.academia.edu/Documents/in/Cell_Cycle?f_ri=1970697","nofollow":true},{"id":23067,"name":"DNA repair","url":"https://www.academia.edu/Documents/in/DNA_repair?f_ri=1970697","nofollow":true},{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true},{"id":74780,"name":"Mutation","url":"https://www.academia.edu/Documents/in/Mutation?f_ri=1970697","nofollow":true},{"id":95192,"name":"Intrinsically disordered proteins","url":"https://www.academia.edu/Documents/in/Intrinsically_disordered_proteins?f_ri=1970697"},{"id":333604,"name":"Schizosaccharomyces Pombe","url":"https://www.academia.edu/Documents/in/Schizosaccharomyces_Pombe?f_ri=1970697"},{"id":653665,"name":"Protein Conformation","url":"https://www.academia.edu/Documents/in/Protein_Conformation?f_ri=1970697"},{"id":663045,"name":"Yeasts","url":"https://www.academia.edu/Documents/in/Yeasts?f_ri=1970697"},{"id":809881,"name":"Amino Acid Sequence","url":"https://www.academia.edu/Documents/in/Amino_Acid_Sequence?f_ri=1970697"},{"id":830071,"name":"Ribonucleotide Reductase","url":"https://www.academia.edu/Documents/in/Ribonucleotide_Reductase?f_ri=1970697"},{"id":983317,"name":"Cell Cycle Proteins","url":"https://www.academia.edu/Documents/in/Cell_Cycle_Proteins?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_5466094" data-work_id="5466094" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/5466094/Allosteric_effectors_do_not_alter_the_oxygen_affinity_of_hemoglobin_crystals">Allosteric effectors do not alter the oxygen affinity of hemoglobin crystals</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">In solution, the oxygen affinity of hemoglobin in the T quaternary structure is decreased in the presence of allosteric effectors such as protons and organic phosphates. To explain these effects, as well as the absence of the Bohr effect... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_5466094" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">In solution, the oxygen affinity of hemoglobin in the T quaternary structure is decreased in the presence of allosteric effectors such as protons and organic phosphates. To explain these effects, as well as the absence of the Bohr effect and the lower oxygen affinity of G-state hemoglobin in the crystal compared to solution, Rivetti C et al. (1993a, Biochemistry52:2888–2906) suggested that there are high- and low-affinity subunit conformations of G, associated with broken and unbroken intersubunit salt bridges. In this model, the crystal of G-state hemoglobin has the lowest possible oxygen affinity because the salt bridges remain intact upon oxygenation. Binding of allosteric effectors in the crystal should therefore not influence the oxygen affinity. To test this hypothesis, we used polarized absorption spectroscopy to measure oxygen binding curves of single crystals of hemoglobin in the T quaternary structure in the presence of the “strong” allosteric effectors, inositol hexaphosphate and bezafibrate. In solution, these effectors reduce the oxygen affinity of the T state by 10-30-fold. We find no change in affinity (<10%) of the crystal. The crystal binding curve, moreover, is noncooperative, which is consistent with the essential feature of the two-state allosteric model of Monod J, Wyman J, and Changeux JP (1965, J Mol Biol12:88–118) that cooperative binding requires a change in quaternary structure. Noncooperative binding by the crystal is not caused by cooperative interactions being masked by fortuitous compensation from a difference in the affinity of the α and β subunits. This was shown by calculating the separate α and β subunit binding curves from the two sets of polarized optical spectra using geometric factors from the X-ray structures of deoxygenated and fully oxygenated T-state molecules determined by Paoli M et al. (1996, J Mol Biol256:775–792).</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/5466094" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="9c64b63ef71d73a0d5057ddf52ef6815" rel="nofollow" data-download="{"attachment_id":49281800,"asset_id":5466094,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/49281800/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="7674674" href="https://independent.academia.edu/andreamozzarelli">andrea mozzarelli</a><script data-card-contents-for-user="7674674" type="text/json">{"id":7674674,"first_name":"andrea","last_name":"mozzarelli","domain_name":"independent","page_name":"andreamozzarelli","display_name":"andrea mozzarelli","profile_url":"https://independent.academia.edu/andreamozzarelli?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_5466094 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="5466094"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 5466094, container: ".js-paper-rank-work_5466094", }); 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$(".js-view-count[data-work-id=5466094]").text(description); $(".js-view-count-work_5466094").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_5466094").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="5466094"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">9</a>  </div><span class="InlineList-item-text u-textTruncate u-pl9x"><a class="InlineList-item-text" data-has-card-for-ri="4987" rel="nofollow" href="https://www.academia.edu/Documents/in/Kinetics">Kinetics</a>, <script data-card-contents-for-ri="4987" type="text/json">{"id":4987,"name":"Kinetics","url":"https://www.academia.edu/Documents/in/Kinetics?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="8914" rel="nofollow" href="https://www.academia.edu/Documents/in/Protein_Science">Protein Science</a>, <script data-card-contents-for-ri="8914" type="text/json">{"id":8914,"name":"Protein Science","url":"https://www.academia.edu/Documents/in/Protein_Science?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="12597" rel="nofollow" href="https://www.academia.edu/Documents/in/Crystallization">Crystallization</a>, <script data-card-contents-for-ri="12597" type="text/json">{"id":12597,"name":"Crystallization","url":"https://www.academia.edu/Documents/in/Crystallization?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="380825" rel="nofollow" href="https://www.academia.edu/Documents/in/Oxygen">Oxygen</a><script data-card-contents-for-ri="380825" type="text/json">{"id":380825,"name":"Oxygen","url":"https://www.academia.edu/Documents/in/Oxygen?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=5466094]'), work: {"id":5466094,"title":"Allosteric effectors do not alter the oxygen affinity of hemoglobin crystals","created_at":"2013-12-17T23:07:45.645-08:00","url":"https://www.academia.edu/5466094/Allosteric_effectors_do_not_alter_the_oxygen_affinity_of_hemoglobin_crystals?f_ri=1970697","dom_id":"work_5466094","summary":"In solution, the oxygen affinity of hemoglobin in the T quaternary structure is decreased in the presence of allosteric effectors such as protons and organic phosphates. To explain these effects, as well as the absence of the Bohr effect and the lower oxygen affinity of G-state hemoglobin in the crystal compared to solution, Rivetti C et al. (1993a, Biochemistry52:2888–2906) suggested that there are high- and low-affinity subunit conformations of G, associated with broken and unbroken intersubunit salt bridges. In this model, the crystal of G-state hemoglobin has the lowest possible oxygen affinity because the salt bridges remain intact upon oxygenation. Binding of allosteric effectors in the crystal should therefore not influence the oxygen affinity. To test this hypothesis, we used polarized absorption spectroscopy to measure oxygen binding curves of single crystals of hemoglobin in the T quaternary structure in the presence of the “strong” allosteric effectors, inositol hexaphosphate and bezafibrate. In solution, these effectors reduce the oxygen affinity of the T state by 10-30-fold. We find no change in affinity (\u003c10%) of the crystal. The crystal binding curve, moreover, is noncooperative, which is consistent with the essential feature of the two-state allosteric model of Monod J, Wyman J, and Changeux JP (1965, J Mol Biol12:88–118) that cooperative binding requires a change in quaternary structure. Noncooperative binding by the crystal is not caused by cooperative interactions being masked by fortuitous compensation from a difference in the affinity of the α and β subunits. This was shown by calculating the separate α and β subunit binding curves from the two sets of polarized optical spectra using geometric factors from the X-ray structures of deoxygenated and fully oxygenated T-state molecules determined by Paoli M et al. (1996, J Mol Biol256:775–792).","downloadable_attachments":[{"id":49281800,"asset_id":5466094,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":7674674,"first_name":"andrea","last_name":"mozzarelli","domain_name":"independent","page_name":"andreamozzarelli","display_name":"andrea mozzarelli","profile_url":"https://independent.academia.edu/andreamozzarelli?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":4987,"name":"Kinetics","url":"https://www.academia.edu/Documents/in/Kinetics?f_ri=1970697","nofollow":true},{"id":8914,"name":"Protein Science","url":"https://www.academia.edu/Documents/in/Protein_Science?f_ri=1970697","nofollow":true},{"id":12597,"name":"Crystallization","url":"https://www.academia.edu/Documents/in/Crystallization?f_ri=1970697","nofollow":true},{"id":380825,"name":"Oxygen","url":"https://www.academia.edu/Documents/in/Oxygen?f_ri=1970697","nofollow":true},{"id":653665,"name":"Protein Conformation","url":"https://www.academia.edu/Documents/in/Protein_Conformation?f_ri=1970697"},{"id":1010725,"name":"Protein Binding","url":"https://www.academia.edu/Documents/in/Protein_Binding?f_ri=1970697"},{"id":1311261,"name":"Hemoglobins","url":"https://www.academia.edu/Documents/in/Hemoglobins?f_ri=1970697"},{"id":1681026,"name":"Biochemistry and cell biology","url":"https://www.academia.edu/Documents/in/Biochemistry_and_cell_biology?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_12334692" data-work_id="12334692" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/12334692/Branched_chain_Amino_Acid_Metabolon_INTERACTION_OF_GLUTAMATE_DEHYDROGENASE_WITH_THE_MITOCHONDRIAL_BRANCHED_CHAIN_AMINOTRANSFERASE_BCATm_">Branched-chain Amino Acid Metabolon INTERACTION OF GLUTAMATE DEHYDROGENASE WITH THE MITOCHONDRIAL BRANCHED-CHAIN AMINOTRANSFERASE (BCATm)</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">The catabolic pathway for branched-chain amino acids includes deamination followed by oxidative decarboxylation of the deaminated product branched-chain ␣-keto acids, catalyzed by the mitochondrial branched-chain aminotransferase (BCATm)... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_12334692" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">The catabolic pathway for branched-chain amino acids includes deamination followed by oxidative decarboxylation of the deaminated product branched-chain ␣-keto acids, catalyzed by the mitochondrial branched-chain aminotransferase (BCATm) and branched-chain ␣-keto acid dehydrogenase enzyme complex (BCKDC). We found that BCATm binds to the E1 decarboxylase of BCKDC, forming a metabolon that allows channeling of branched-chain ␣-keto acids from BCATm to E1. The protein complex also contains glutamate dehydrogenase (GDH1), 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1, pyruvate carboxylase, and BCKDC kinase. GDH1 binds to the pyridoxamine 5-phosphate (PMP) form of BCATm (PMP-BCATm) but not to the pyridoxal 5-phosphate-BCATm and other metabolon proteins. Leucine activates GDH1, and oxidative deamination of glutamate is increased further by addition of PMP-BCATm. Isoleucine and valine are not allosteric activators of GDH1, but in the presence of 5-phosphate-BCATm, they convert BCATm to PMP-BCATm, stimulating GDH1 activity. Sensitivity to ADP activation of GDH1 was unaffected by PMP-BCATm; however, addition of a 3 or higher molar ratio of PMP-BCATm to GDH1 protected GDH1 from GTP inhibition by 50%. Kinetic results suggest that GDH1 facilitates regeneration of the form of BCATm that binds to E1 decarboxylase of the BCKDC, promotes metabolon formation, branched-chain amino acid oxidation, and cycling of nitrogen through glutamate.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/12334692" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="259c80fccd71d0d5d237029363bbeb56" rel="nofollow" data-download="{"attachment_id":46237274,"asset_id":12334692,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/46237274/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="31000812" href="https://independent.academia.edu/MohammadIslam69">Mohammad Islam</a><script data-card-contents-for-user="31000812" type="text/json">{"id":31000812,"first_name":"Mohammad","last_name":"Islam","domain_name":"independent","page_name":"MohammadIslam69","display_name":"Mohammad Islam","profile_url":"https://independent.academia.edu/MohammadIslam69?f_ri=1970697","photo":"https://0.academia-photos.com/31000812/9080623/10128805/s65_mohammad.islam.jpg_oh_c7241eea907b30e3f0c926ee7c6cf146_oe_55cd78b2"}</script></span></span></li><li class="js-paper-rank-work_12334692 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="12334692"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 12334692, container: ".js-paper-rank-work_12334692", }); 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$(".js-view-count[data-work-id=12334692]").text(description); $(".js-view-count-work_12334692").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_12334692").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="12334692"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">16</a>  </div><span class="InlineList-item-text u-textTruncate u-pl10x"><a class="InlineList-item-text" data-has-card-for-ri="15719" rel="nofollow" href="https://www.academia.edu/Documents/in/Mitochondria">Mitochondria</a>, <script data-card-contents-for-ri="15719" type="text/json">{"id":15719,"name":"Mitochondria","url":"https://www.academia.edu/Documents/in/Mitochondria?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="18520" rel="nofollow" href="https://www.academia.edu/Documents/in/Biological_Chemistry">Biological Chemistry</a>, <script data-card-contents-for-ri="18520" type="text/json">{"id":18520,"name":"Biological Chemistry","url":"https://www.academia.edu/Documents/in/Biological_Chemistry?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="35607" rel="nofollow" href="https://www.academia.edu/Documents/in/Biocatalysis">Biocatalysis</a>, <script data-card-contents-for-ri="35607" type="text/json">{"id":35607,"name":"Biocatalysis","url":"https://www.academia.edu/Documents/in/Biocatalysis?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="47884" rel="nofollow" href="https://www.academia.edu/Documents/in/Biological_Sciences">Biological Sciences</a><script data-card-contents-for-ri="47884" type="text/json">{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=12334692]'), work: {"id":12334692,"title":"Branched-chain Amino Acid Metabolon INTERACTION OF GLUTAMATE DEHYDROGENASE WITH THE MITOCHONDRIAL BRANCHED-CHAIN AMINOTRANSFERASE (BCATm)","created_at":"2015-05-11T08:38:06.438-07:00","url":"https://www.academia.edu/12334692/Branched_chain_Amino_Acid_Metabolon_INTERACTION_OF_GLUTAMATE_DEHYDROGENASE_WITH_THE_MITOCHONDRIAL_BRANCHED_CHAIN_AMINOTRANSFERASE_BCATm_?f_ri=1970697","dom_id":"work_12334692","summary":"The catabolic pathway for branched-chain amino acids includes deamination followed by oxidative decarboxylation of the deaminated product branched-chain ␣-keto acids, catalyzed by the mitochondrial branched-chain aminotransferase (BCATm) and branched-chain ␣-keto acid dehydrogenase enzyme complex (BCKDC). We found that BCATm binds to the E1 decarboxylase of BCKDC, forming a metabolon that allows channeling of branched-chain ␣-keto acids from BCATm to E1. The protein complex also contains glutamate dehydrogenase (GDH1), 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1, pyruvate carboxylase, and BCKDC kinase. GDH1 binds to the pyridoxamine 5-phosphate (PMP) form of BCATm (PMP-BCATm) but not to the pyridoxal 5-phosphate-BCATm and other metabolon proteins. Leucine activates GDH1, and oxidative deamination of glutamate is increased further by addition of PMP-BCATm. Isoleucine and valine are not allosteric activators of GDH1, but in the presence of 5-phosphate-BCATm, they convert BCATm to PMP-BCATm, stimulating GDH1 activity. Sensitivity to ADP activation of GDH1 was unaffected by PMP-BCATm; however, addition of a 3 or higher molar ratio of PMP-BCATm to GDH1 protected GDH1 from GTP inhibition by 50%. Kinetic results suggest that GDH1 facilitates regeneration of the form of BCATm that binds to E1 decarboxylase of the BCKDC, promotes metabolon formation, branched-chain amino acid oxidation, and cycling of nitrogen through glutamate.","downloadable_attachments":[{"id":46237274,"asset_id":12334692,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":31000812,"first_name":"Mohammad","last_name":"Islam","domain_name":"independent","page_name":"MohammadIslam69","display_name":"Mohammad Islam","profile_url":"https://independent.academia.edu/MohammadIslam69?f_ri=1970697","photo":"https://0.academia-photos.com/31000812/9080623/10128805/s65_mohammad.islam.jpg_oh_c7241eea907b30e3f0c926ee7c6cf146_oe_55cd78b2"}],"research_interests":[{"id":15719,"name":"Mitochondria","url":"https://www.academia.edu/Documents/in/Mitochondria?f_ri=1970697","nofollow":true},{"id":18520,"name":"Biological Chemistry","url":"https://www.academia.edu/Documents/in/Biological_Chemistry?f_ri=1970697","nofollow":true},{"id":35607,"name":"Biocatalysis","url":"https://www.academia.edu/Documents/in/Biocatalysis?f_ri=1970697","nofollow":true},{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true},{"id":172083,"name":"Phosphorylation","url":"https://www.academia.edu/Documents/in/Phosphorylation?f_ri=1970697"},{"id":201241,"name":"Affinity chromatography","url":"https://www.academia.edu/Documents/in/Affinity_chromatography?f_ri=1970697"},{"id":260118,"name":"CHEMICAL SCIENCES","url":"https://www.academia.edu/Documents/in/CHEMICAL_SCIENCES?f_ri=1970697"},{"id":330039,"name":"Deamination","url":"https://www.academia.edu/Documents/in/Deamination?f_ri=1970697"},{"id":375054,"name":"Rats","url":"https://www.academia.edu/Documents/in/Rats?f_ri=1970697"},{"id":1010725,"name":"Protein Binding","url":"https://www.academia.edu/Documents/in/Protein_Binding?f_ri=1970697"},{"id":1256747,"name":"Oxidation-Reduction","url":"https://www.academia.edu/Documents/in/Oxidation-Reduction?f_ri=1970697"},{"id":1292327,"name":"Metabolome","url":"https://www.academia.edu/Documents/in/Metabolome?f_ri=1970697"},{"id":1375237,"name":"Glutamate Dehydrogenase","url":"https://www.academia.edu/Documents/in/Glutamate_Dehydrogenase?f_ri=1970697"},{"id":1902574,"name":"Decarboxylation","url":"https://www.academia.edu/Documents/in/Decarboxylation?f_ri=1970697"},{"id":1929051,"name":"Transaminases","url":"https://www.academia.edu/Documents/in/Transaminases?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_21992752" data-work_id="21992752" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/21992752/Principles_of_Protein_Protein_Interactions_What_are_the_Preferred_Ways_For_Proteins_To_Interact">Principles of Protein−Protein Interactions: What are the Preferred Ways For Proteins To Interact?</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest">University. Dr. Gursoy's research interests are in the area of computational biology, particularly protein interactions and highperformance algorithms for computational biology.</div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/21992752" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="e84ad75414039f46c9803c79f57619a2" rel="nofollow" data-download="{"attachment_id":42698694,"asset_id":21992752,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/42698694/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="43249184" href="https://independent.academia.edu/BuyongMa">Buyong Ma</a><script data-card-contents-for-user="43249184" type="text/json">{"id":43249184,"first_name":"Buyong","last_name":"Ma","domain_name":"independent","page_name":"BuyongMa","display_name":"Buyong Ma","profile_url":"https://independent.academia.edu/BuyongMa?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_21992752 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="21992752"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 21992752, container: ".js-paper-rank-work_21992752", }); });</script></li><li class="js-percentile-work_21992752 InlineList-item InlineList-item--bordered hidden u-tcGrayDark"><span class="percentile-widget hidden"><span class="u-mr2x percentile-widget" style="display: none">•</span><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 21992752; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-percentile-work_21992752"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></li><li class="js-view-count-work_21992752 InlineList-item InlineList-item--bordered hidden"><div><span><span class="js-view-count view-count u-mr2x" data-work-id="21992752"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 21992752; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=21992752]").text(description); $(".js-view-count-work_21992752").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_21992752").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="21992752"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">6</a>  </div><span class="InlineList-item-text u-textTruncate u-pl9x"><a class="InlineList-item-text" data-has-card-for-ri="50487" rel="nofollow" href="https://www.academia.edu/Documents/in/Protein-Protein_Interaction">Protein-Protein Interaction</a>, <script data-card-contents-for-ri="50487" type="text/json">{"id":50487,"name":"Protein-Protein Interaction","url":"https://www.academia.edu/Documents/in/Protein-Protein_Interaction?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="181569" rel="nofollow" href="https://www.academia.edu/Documents/in/Proteins">Proteins</a>, <script data-card-contents-for-ri="181569" type="text/json">{"id":181569,"name":"Proteins","url":"https://www.academia.edu/Documents/in/Proteins?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="260118" rel="nofollow" href="https://www.academia.edu/Documents/in/CHEMICAL_SCIENCES">CHEMICAL SCIENCES</a>, <script data-card-contents-for-ri="260118" type="text/json">{"id":260118,"name":"CHEMICAL SCIENCES","url":"https://www.academia.edu/Documents/in/CHEMICAL_SCIENCES?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="653665" rel="nofollow" href="https://www.academia.edu/Documents/in/Protein_Conformation">Protein Conformation</a><script data-card-contents-for-ri="653665" type="text/json">{"id":653665,"name":"Protein Conformation","url":"https://www.academia.edu/Documents/in/Protein_Conformation?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=21992752]'), work: {"id":21992752,"title":"Principles of Protein−Protein Interactions: What are the Preferred Ways For Proteins To Interact?","created_at":"2016-02-15T04:11:24.168-08:00","url":"https://www.academia.edu/21992752/Principles_of_Protein_Protein_Interactions_What_are_the_Preferred_Ways_For_Proteins_To_Interact?f_ri=1970697","dom_id":"work_21992752","summary":"University. Dr. Gursoy's research interests are in the area of computational biology, particularly protein interactions and highperformance algorithms for computational biology.","downloadable_attachments":[{"id":42698694,"asset_id":21992752,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":43249184,"first_name":"Buyong","last_name":"Ma","domain_name":"independent","page_name":"BuyongMa","display_name":"Buyong Ma","profile_url":"https://independent.academia.edu/BuyongMa?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":50487,"name":"Protein-Protein Interaction","url":"https://www.academia.edu/Documents/in/Protein-Protein_Interaction?f_ri=1970697","nofollow":true},{"id":181569,"name":"Proteins","url":"https://www.academia.edu/Documents/in/Proteins?f_ri=1970697","nofollow":true},{"id":260118,"name":"CHEMICAL SCIENCES","url":"https://www.academia.edu/Documents/in/CHEMICAL_SCIENCES?f_ri=1970697","nofollow":true},{"id":653665,"name":"Protein Conformation","url":"https://www.academia.edu/Documents/in/Protein_Conformation?f_ri=1970697","nofollow":true},{"id":1010725,"name":"Protein Binding","url":"https://www.academia.edu/Documents/in/Protein_Binding?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_21012994" data-work_id="21012994" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/21012994/2_Aminothienopyridazines_as_Novel_Adenosine_A_1_Receptor_Allosteric_Modulators_and_Antagonists">2-Aminothienopyridazines as Novel Adenosine A 1 Receptor Allosteric Modulators and Antagonists</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">A pharmacophore-based screen identified 32 compounds including ethyl 5-amino-3-(4-tertbutylphenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxylate (8) as a new allosteric modulator of the adenosine A 1 receptor (A 1 AR). On the... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_21012994" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">A pharmacophore-based screen identified 32 compounds including ethyl 5-amino-3-(4-tertbutylphenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxylate (8) as a new allosteric modulator of the adenosine A 1 receptor (A 1 AR). On the basis of this lead, various derivatives were prepared and evaluated for activity at the human A 1 AR. A number of the test compounds allosterically stabilized agonist-receptor-G protein ternary complexes in dissociation kinetic assays, but were found to be more potent as antagonists in subsequent functional assays of ERK1/2 phosphorylation. Additional experiments on the most potent antagonist, 13b, investigating A 1 ARmediated [ 35 S]GTPγS binding and [ 3 H]CCPA equilibrium binding confirmed its antagonistic mode of action and also identified inverse agonism. This study has thus identified a new class of A 1 AR antagonists that can also recognize the receptor's allosteric site with lower potency.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/21012994" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="a9a71a134b9032b8f09afa9a4c81afaa" rel="nofollow" data-download="{"attachment_id":41670908,"asset_id":21012994,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/41670908/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="32694315" href="https://monash.academia.edu/DavidChalmers">David Chalmers</a><script data-card-contents-for-user="32694315" type="text/json">{"id":32694315,"first_name":"David","last_name":"Chalmers","domain_name":"monash","page_name":"DavidChalmers","display_name":"David Chalmers","profile_url":"https://monash.academia.edu/DavidChalmers?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_21012994 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="21012994"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 21012994, container: ".js-paper-rank-work_21012994", }); 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$(".js-view-count[data-work-id=21012994]").text(description); $(".js-view-count-work_21012994").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_21012994").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="21012994"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">6</a>  </div><span class="InlineList-item-text u-textTruncate u-pl9x"><a class="InlineList-item-text" data-has-card-for-ri="531" rel="nofollow" href="https://www.academia.edu/Documents/in/Organic_Chemistry">Organic Chemistry</a>, <script data-card-contents-for-ri="531" type="text/json">{"id":531,"name":"Organic Chemistry","url":"https://www.academia.edu/Documents/in/Organic_Chemistry?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="2375" rel="nofollow" href="https://www.academia.edu/Documents/in/Medicinal_Chemistry">Medicinal Chemistry</a>, <script data-card-contents-for-ri="2375" type="text/json">{"id":2375,"name":"Medicinal Chemistry","url":"https://www.academia.edu/Documents/in/Medicinal_Chemistry?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="4987" rel="nofollow" href="https://www.academia.edu/Documents/in/Kinetics">Kinetics</a>, <script data-card-contents-for-ri="4987" type="text/json">{"id":4987,"name":"Kinetics","url":"https://www.academia.edu/Documents/in/Kinetics?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="967839" rel="nofollow" href="https://www.academia.edu/Documents/in/Structure_activity_Relationship">Structure activity Relationship</a><script data-card-contents-for-ri="967839" type="text/json">{"id":967839,"name":"Structure activity Relationship","url":"https://www.academia.edu/Documents/in/Structure_activity_Relationship?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=21012994]'), work: {"id":21012994,"title":"2-Aminothienopyridazines as Novel Adenosine A 1 Receptor Allosteric Modulators and Antagonists","created_at":"2016-01-27T22:34:40.532-08:00","url":"https://www.academia.edu/21012994/2_Aminothienopyridazines_as_Novel_Adenosine_A_1_Receptor_Allosteric_Modulators_and_Antagonists?f_ri=1970697","dom_id":"work_21012994","summary":"A pharmacophore-based screen identified 32 compounds including ethyl 5-amino-3-(4-tertbutylphenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxylate (8) as a new allosteric modulator of the adenosine A 1 receptor (A 1 AR). On the basis of this lead, various derivatives were prepared and evaluated for activity at the human A 1 AR. A number of the test compounds allosterically stabilized agonist-receptor-G protein ternary complexes in dissociation kinetic assays, but were found to be more potent as antagonists in subsequent functional assays of ERK1/2 phosphorylation. Additional experiments on the most potent antagonist, 13b, investigating A 1 ARmediated [ 35 S]GTPγS binding and [ 3 H]CCPA equilibrium binding confirmed its antagonistic mode of action and also identified inverse agonism. This study has thus identified a new class of A 1 AR antagonists that can also recognize the receptor's allosteric site with lower potency.","downloadable_attachments":[{"id":41670908,"asset_id":21012994,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":32694315,"first_name":"David","last_name":"Chalmers","domain_name":"monash","page_name":"DavidChalmers","display_name":"David Chalmers","profile_url":"https://monash.academia.edu/DavidChalmers?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":531,"name":"Organic Chemistry","url":"https://www.academia.edu/Documents/in/Organic_Chemistry?f_ri=1970697","nofollow":true},{"id":2375,"name":"Medicinal Chemistry","url":"https://www.academia.edu/Documents/in/Medicinal_Chemistry?f_ri=1970697","nofollow":true},{"id":4987,"name":"Kinetics","url":"https://www.academia.edu/Documents/in/Kinetics?f_ri=1970697","nofollow":true},{"id":967839,"name":"Structure activity Relationship","url":"https://www.academia.edu/Documents/in/Structure_activity_Relationship?f_ri=1970697","nofollow":true},{"id":1724844,"name":"Molecular Structure","url":"https://www.academia.edu/Documents/in/Molecular_Structure?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_12361889" data-work_id="12361889" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/12361889/HPLC_Based_Activity_Profiling_Discovery_of_Piperine_as_a_Positive_GABAA_Receptor_Modulator_Targeting_a_Benzodiazepine_Independent_Binding_Site">HPLC-Based Activity Profiling: Discovery of Piperine as a Positive GABAA Receptor Modulator Targeting a Benzodiazepine-Independent Binding Site</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">A plant extract library was screened for GABA A receptor activity making use of a twomicroelectrode voltage clamp assay on Xenopus laevis oocytes. An ethyl acetate extract of black pepper fruits [Piper nigrum L. (Piperaceae) 100 μg/mL]... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_12361889" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">A plant extract library was screened for GABA A receptor activity making use of a twomicroelectrode voltage clamp assay on Xenopus laevis oocytes. An ethyl acetate extract of black pepper fruits [Piper nigrum L. (Piperaceae) 100 μg/mL] potentiated GABA-induced chloride currents through GABA A receptors (composed of α 1 , β 2 , and γ 2S subunits) by 169.1 ± 2.4%.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/12361889" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="4797762a2bfed63cf7390ed0e0c5f576" rel="nofollow" data-download="{"attachment_id":46222841,"asset_id":12361889,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/46222841/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="31072728" href="https://independent.academia.edu/HamburgerMatthias">Matthias Hamburger</a><script data-card-contents-for-user="31072728" type="text/json">{"id":31072728,"first_name":"Matthias","last_name":"Hamburger","domain_name":"independent","page_name":"HamburgerMatthias","display_name":"Matthias Hamburger","profile_url":"https://independent.academia.edu/HamburgerMatthias?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_12361889 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="12361889"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 12361889, container: ".js-paper-rank-work_12361889", }); });</script></li><li class="js-percentile-work_12361889 InlineList-item InlineList-item--bordered hidden u-tcGrayDark"><span class="percentile-widget hidden"><span class="u-mr2x percentile-widget" style="display: none">•</span><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 12361889; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-percentile-work_12361889"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></li><li class="js-view-count-work_12361889 InlineList-item InlineList-item--bordered hidden"><div><span><span class="js-view-count view-count u-mr2x" data-work-id="12361889"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 12361889; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=12361889]").text(description); $(".js-view-count-work_12361889").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_12361889").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="12361889"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">22</a>  </div><span class="InlineList-item-text u-textTruncate u-pl10x"><a class="InlineList-item-text" data-has-card-for-ri="2168" rel="nofollow" href="https://www.academia.edu/Documents/in/Natural_Products">Natural Products</a>, <script data-card-contents-for-ri="2168" type="text/json">{"id":2168,"name":"Natural Products","url":"https://www.academia.edu/Documents/in/Natural_Products?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="14080" rel="nofollow" href="https://www.academia.edu/Documents/in/Pharmacognosy">Pharmacognosy</a>, <script data-card-contents-for-ri="14080" type="text/json">{"id":14080,"name":"Pharmacognosy","url":"https://www.academia.edu/Documents/in/Pharmacognosy?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="47884" rel="nofollow" href="https://www.academia.edu/Documents/in/Biological_Sciences">Biological Sciences</a>, <script data-card-contents-for-ri="47884" type="text/json">{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="59370" rel="nofollow" href="https://www.academia.edu/Documents/in/In_Vitro">In Vitro</a><script data-card-contents-for-ri="59370" type="text/json">{"id":59370,"name":"In Vitro","url":"https://www.academia.edu/Documents/in/In_Vitro?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=12361889]'), work: {"id":12361889,"title":"HPLC-Based Activity Profiling: Discovery of Piperine as a Positive GABAA Receptor Modulator Targeting a Benzodiazepine-Independent Binding Site","created_at":"2015-05-13T00:13:01.145-07:00","url":"https://www.academia.edu/12361889/HPLC_Based_Activity_Profiling_Discovery_of_Piperine_as_a_Positive_GABAA_Receptor_Modulator_Targeting_a_Benzodiazepine_Independent_Binding_Site?f_ri=1970697","dom_id":"work_12361889","summary":"A plant extract library was screened for GABA A receptor activity making use of a twomicroelectrode voltage clamp assay on Xenopus laevis oocytes. An ethyl acetate extract of black pepper fruits [Piper nigrum L. (Piperaceae) 100 μg/mL] potentiated GABA-induced chloride currents through GABA A receptors (composed of α 1 , β 2 , and γ 2S subunits) by 169.1 ± 2.4%.","downloadable_attachments":[{"id":46222841,"asset_id":12361889,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":31072728,"first_name":"Matthias","last_name":"Hamburger","domain_name":"independent","page_name":"HamburgerMatthias","display_name":"Matthias Hamburger","profile_url":"https://independent.academia.edu/HamburgerMatthias?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":2168,"name":"Natural Products","url":"https://www.academia.edu/Documents/in/Natural_Products?f_ri=1970697","nofollow":true},{"id":14080,"name":"Pharmacognosy","url":"https://www.academia.edu/Documents/in/Pharmacognosy?f_ri=1970697","nofollow":true},{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true},{"id":59370,"name":"In Vitro","url":"https://www.academia.edu/Documents/in/In_Vitro?f_ri=1970697","nofollow":true},{"id":133351,"name":"Benzodiazepines","url":"https://www.academia.edu/Documents/in/Benzodiazepines?f_ri=1970697"},{"id":160814,"name":"Fruit","url":"https://www.academia.edu/Documents/in/Fruit?f_ri=1970697"},{"id":161562,"name":"Alkaloids","url":"https://www.academia.edu/Documents/in/Alkaloids?f_ri=1970697"},{"id":206470,"name":"Piper nigrum","url":"https://www.academia.edu/Documents/in/Piper_nigrum?f_ri=1970697"},{"id":246560,"name":"High Pressure Liquid Chromatography","url":"https://www.academia.edu/Documents/in/High_Pressure_Liquid_Chromatography?f_ri=1970697"},{"id":260118,"name":"CHEMICAL SCIENCES","url":"https://www.academia.edu/Documents/in/CHEMICAL_SCIENCES?f_ri=1970697"},{"id":309895,"name":"Isolation","url":"https://www.academia.edu/Documents/in/Isolation?f_ri=1970697"},{"id":375054,"name":"Rats","url":"https://www.academia.edu/Documents/in/Rats?f_ri=1970697"},{"id":460256,"name":"Natural","url":"https://www.academia.edu/Documents/in/Natural?f_ri=1970697"},{"id":477264,"name":"Xenopus laevis","url":"https://www.academia.edu/Documents/in/Xenopus_laevis?f_ri=1970697"},{"id":783432,"name":"Biological activity","url":"https://www.academia.edu/Documents/in/Biological_activity?f_ri=1970697"},{"id":956315,"name":"Oocytes","url":"https://www.academia.edu/Documents/in/Oocytes?f_ri=1970697"},{"id":1242506,"name":"Binding Site","url":"https://www.academia.edu/Documents/in/Binding_Site?f_ri=1970697"},{"id":1293238,"name":"Oocyte","url":"https://www.academia.edu/Documents/in/Oocyte?f_ri=1970697"},{"id":1724844,"name":"Molecular Structure","url":"https://www.academia.edu/Documents/in/Molecular_Structure?f_ri=1970697"},{"id":1880638,"name":"Piperidines","url":"https://www.academia.edu/Documents/in/Piperidines?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"},{"id":2223059,"name":"Flumazenil","url":"https://www.academia.edu/Documents/in/Flumazenil?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_22476104" data-work_id="22476104" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/22476104/Metabotropic_glutamate_receptors_as_therapeutic_targets_for_schizophrenia">Metabotropic glutamate receptors as therapeutic targets for schizophrenia</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">Treatment options for schizophrenia that address all symptom categories (positive, negative, and cognitive) are lacking in current therapies for this disorder. Compounds targeting the metabotropic glutamate (mGlu) receptors hold promise... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_22476104" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">Treatment options for schizophrenia that address all symptom categories (positive, negative, and cognitive) are lacking in current therapies for this disorder. Compounds targeting the metabotropic glutamate (mGlu) receptors hold promise as a more comprehensive therapeutic alternative to typical and atypical antipsychotics and may avoid the occurrence of extrapyramidal side effects that accompany these treatments. Activation of the group II mGlu receptors (mGlu 2 and mGlu 3 ) and the group I mGlu 5 are hypothesized to normalize the disruption of thalamocortical glutamatergic circuitry that results in abnormal glutamaterigic signaling in the prefrontal cortex (PFC). Agonists of mGlu 2 and mGlu 3 have demonstrated efficacy for the positive symptom group in both animal models and clinical trials with mGlu 2 being the subtype most likely responsible for the therapeutic effect. Limitations in the chemical space tolerated by the orthosteric site of the mGlu receptors has led to the pursuit of compounds that potentiate the receptor's response to glutamate by acting at less highly conserved allosteric sites. Several series of selective positive allosteric modulators (PAMs) for mGlu 2 and mGlu 5 have demonstrated efficacy in animal models used for the evaluation of antipsychotic agents. In addition, evidence from animal studies indicates that mGlu 5 PAMs hold promise for the treatment of cognitive deficits that occur in schizophrenia. Hopefully, further optimization of allosteric modulators of mGlu receptors will yield clinical candidates that will allow full evaluation of the potential efficacy of these compounds in the treatment of multiple symptom domains in schizophrenia patients in the near future.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/22476104" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="4760f15ba17784334285c392ffb6589d" rel="nofollow" data-download="{"attachment_id":43097700,"asset_id":22476104,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/43097700/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="43982549" href="https://independent.academia.edu/ConnJeffrey">Jeffrey Conn</a><script data-card-contents-for-user="43982549" type="text/json">{"id":43982549,"first_name":"Jeffrey","last_name":"Conn","domain_name":"independent","page_name":"ConnJeffrey","display_name":"Jeffrey Conn","profile_url":"https://independent.academia.edu/ConnJeffrey?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_22476104 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="22476104"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 22476104, container: ".js-paper-rank-work_22476104", }); });</script></li><li class="js-percentile-work_22476104 InlineList-item InlineList-item--bordered hidden u-tcGrayDark"><span class="percentile-widget hidden"><span class="u-mr2x percentile-widget" style="display: none">•</span><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 22476104; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-percentile-work_22476104"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></li><li class="js-view-count-work_22476104 InlineList-item InlineList-item--bordered hidden"><div><span><span class="js-view-count view-count u-mr2x" data-work-id="22476104"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 22476104; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=22476104]").text(description); $(".js-view-count-work_22476104").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_22476104").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="22476104"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">15</a>  </div><span class="InlineList-item-text u-textTruncate u-pl10x"><a class="InlineList-item-text" data-has-card-for-ri="221" rel="nofollow" href="https://www.academia.edu/Documents/in/Psychology">Psychology</a>, <script data-card-contents-for-ri="221" type="text/json">{"id":221,"name":"Psychology","url":"https://www.academia.edu/Documents/in/Psychology?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="3227" rel="nofollow" href="https://www.academia.edu/Documents/in/Schizophrenia">Schizophrenia</a>, <script data-card-contents-for-ri="3227" type="text/json">{"id":3227,"name":"Schizophrenia","url":"https://www.academia.edu/Documents/in/Schizophrenia?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="3233" rel="nofollow" href="https://www.academia.edu/Documents/in/Animal_Studies">Animal Studies</a>, <script data-card-contents-for-ri="3233" type="text/json">{"id":3233,"name":"Animal Studies","url":"https://www.academia.edu/Documents/in/Animal_Studies?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="4531" rel="nofollow" href="https://www.academia.edu/Documents/in/Clinical_Trial">Clinical Trial</a><script data-card-contents-for-ri="4531" type="text/json">{"id":4531,"name":"Clinical Trial","url":"https://www.academia.edu/Documents/in/Clinical_Trial?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=22476104]'), work: {"id":22476104,"title":"Metabotropic glutamate receptors as therapeutic targets for schizophrenia","created_at":"2016-02-26T06:13:51.483-08:00","url":"https://www.academia.edu/22476104/Metabotropic_glutamate_receptors_as_therapeutic_targets_for_schizophrenia?f_ri=1970697","dom_id":"work_22476104","summary":"Treatment options for schizophrenia that address all symptom categories (positive, negative, and cognitive) are lacking in current therapies for this disorder. Compounds targeting the metabotropic glutamate (mGlu) receptors hold promise as a more comprehensive therapeutic alternative to typical and atypical antipsychotics and may avoid the occurrence of extrapyramidal side effects that accompany these treatments. Activation of the group II mGlu receptors (mGlu 2 and mGlu 3 ) and the group I mGlu 5 are hypothesized to normalize the disruption of thalamocortical glutamatergic circuitry that results in abnormal glutamaterigic signaling in the prefrontal cortex (PFC). Agonists of mGlu 2 and mGlu 3 have demonstrated efficacy for the positive symptom group in both animal models and clinical trials with mGlu 2 being the subtype most likely responsible for the therapeutic effect. Limitations in the chemical space tolerated by the orthosteric site of the mGlu receptors has led to the pursuit of compounds that potentiate the receptor's response to glutamate by acting at less highly conserved allosteric sites. Several series of selective positive allosteric modulators (PAMs) for mGlu 2 and mGlu 5 have demonstrated efficacy in animal models used for the evaluation of antipsychotic agents. In addition, evidence from animal studies indicates that mGlu 5 PAMs hold promise for the treatment of cognitive deficits that occur in schizophrenia. Hopefully, further optimization of allosteric modulators of mGlu receptors will yield clinical candidates that will allow full evaluation of the potential efficacy of these compounds in the treatment of multiple symptom domains in schizophrenia patients in the near future.","downloadable_attachments":[{"id":43097700,"asset_id":22476104,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":43982549,"first_name":"Jeffrey","last_name":"Conn","domain_name":"independent","page_name":"ConnJeffrey","display_name":"Jeffrey Conn","profile_url":"https://independent.academia.edu/ConnJeffrey?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":221,"name":"Psychology","url":"https://www.academia.edu/Documents/in/Psychology?f_ri=1970697","nofollow":true},{"id":3227,"name":"Schizophrenia","url":"https://www.academia.edu/Documents/in/Schizophrenia?f_ri=1970697","nofollow":true},{"id":3233,"name":"Animal Studies","url":"https://www.academia.edu/Documents/in/Animal_Studies?f_ri=1970697","nofollow":true},{"id":4531,"name":"Clinical Trial","url":"https://www.academia.edu/Documents/in/Clinical_Trial?f_ri=1970697","nofollow":true},{"id":7955,"name":"Neuropharmacology","url":"https://www.academia.edu/Documents/in/Neuropharmacology?f_ri=1970697"},{"id":28576,"name":"Prefrontal Cortex","url":"https://www.academia.edu/Documents/in/Prefrontal_Cortex?f_ri=1970697"},{"id":61233,"name":"Glutamate","url":"https://www.academia.edu/Documents/in/Glutamate?f_ri=1970697"},{"id":151951,"name":"Animal Model","url":"https://www.academia.edu/Documents/in/Animal_Model?f_ri=1970697"},{"id":159187,"name":"Drug Delivery Systems","url":"https://www.academia.edu/Documents/in/Drug_Delivery_Systems?f_ri=1970697"},{"id":530709,"name":"Atypical Antipsychotics","url":"https://www.academia.edu/Documents/in/Atypical_Antipsychotics?f_ri=1970697"},{"id":637718,"name":"Nervous System","url":"https://www.academia.edu/Documents/in/Nervous_System?f_ri=1970697"},{"id":698785,"name":"Side Effect","url":"https://www.academia.edu/Documents/in/Side_Effect?f_ri=1970697"},{"id":1239755,"name":"Neurosciences","url":"https://www.academia.edu/Documents/in/Neurosciences?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"},{"id":2012816,"name":"Glutamate Receptor","url":"https://www.academia.edu/Documents/in/Glutamate_Receptor?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_26524407" data-work_id="26524407" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/26524407/Mechanism_and_Specificity_of_Pentachloropseudilin_mediated_Inhibition_of_Myosin_Motor_Activity">Mechanism and Specificity of Pentachloropseudilin-mediated Inhibition of Myosin Motor Activity</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">Here, we report that the natural compound pentachloropseudilin (PClP) acts as a reversible and allosteric inhibitor of myosin ATPase and motor activity. IC 50 values are in the range from 1 to 5 M for mammalian class-1 myosins and greater... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_26524407" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">Here, we report that the natural compound pentachloropseudilin (PClP) acts as a reversible and allosteric inhibitor of myosin ATPase and motor activity. IC 50 values are in the range from 1 to 5 M for mammalian class-1 myosins and greater than 90 M for class-2 and class-5 myosins, and no inhibition was observed with class-6 and class-7 myosins. We show that in mammalian cells, PClP selectively inhibits myosin-1c function. To elucidate the structural basis for PClP-induced allosteric coupling and isoform-specific differences in the inhibitory potency of the compound, we used a multifaceted approach combining direct functional, crystallographic, and in silico modeling studies. Our results indicate that allosteric inhibition by PClP is mediated by the combined effects of global changes in protein dynamics and direct communication between the catalytic and allosteric sites via a cascade of small conformational changes along a conserved communication pathway.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/26524407" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="ee338515b5bb28f695bbe8174dc052db" rel="nofollow" data-download="{"attachment_id":46820786,"asset_id":26524407,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/46820786/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="14158350" href="https://mh-hannover.academia.edu/DietmarManstein">Dietmar Manstein</a><script data-card-contents-for-user="14158350" type="text/json">{"id":14158350,"first_name":"Dietmar","last_name":"Manstein","domain_name":"mh-hannover","page_name":"DietmarManstein","display_name":"Dietmar Manstein","profile_url":"https://mh-hannover.academia.edu/DietmarManstein?f_ri=1970697","photo":"https://0.academia-photos.com/14158350/3891000/14578053/s65_dietmar.manstein.jpg"}</script></span></span></li><li class="js-paper-rank-work_26524407 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="26524407"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 26524407, container: ".js-paper-rank-work_26524407", }); 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$(".js-view-count[data-work-id=26524407]").text(description); $(".js-view-count-work_26524407").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_26524407").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="26524407"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">8</a>  </div><span class="InlineList-item-text u-textTruncate u-pl9x"><a class="InlineList-item-text" data-has-card-for-ri="18520" rel="nofollow" href="https://www.academia.edu/Documents/in/Biological_Chemistry">Biological Chemistry</a>, <script data-card-contents-for-ri="18520" type="text/json">{"id":18520,"name":"Biological Chemistry","url":"https://www.academia.edu/Documents/in/Biological_Chemistry?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="47884" rel="nofollow" href="https://www.academia.edu/Documents/in/Biological_Sciences">Biological Sciences</a>, <script data-card-contents-for-ri="47884" type="text/json">{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="170274" rel="nofollow" href="https://www.academia.edu/Documents/in/Dictyostelium">Dictyostelium</a>, <script data-card-contents-for-ri="170274" type="text/json">{"id":170274,"name":"Dictyostelium","url":"https://www.academia.edu/Documents/in/Dictyostelium?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="260118" rel="nofollow" href="https://www.academia.edu/Documents/in/CHEMICAL_SCIENCES">CHEMICAL SCIENCES</a><script data-card-contents-for-ri="260118" type="text/json">{"id":260118,"name":"CHEMICAL SCIENCES","url":"https://www.academia.edu/Documents/in/CHEMICAL_SCIENCES?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=26524407]'), work: {"id":26524407,"title":"Mechanism and Specificity of Pentachloropseudilin-mediated Inhibition of Myosin Motor Activity","created_at":"2016-06-26T23:51:19.311-07:00","url":"https://www.academia.edu/26524407/Mechanism_and_Specificity_of_Pentachloropseudilin_mediated_Inhibition_of_Myosin_Motor_Activity?f_ri=1970697","dom_id":"work_26524407","summary":"Here, we report that the natural compound pentachloropseudilin (PClP) acts as a reversible and allosteric inhibitor of myosin ATPase and motor activity. IC 50 values are in the range from 1 to 5 M for mammalian class-1 myosins and greater than 90 M for class-2 and class-5 myosins, and no inhibition was observed with class-6 and class-7 myosins. We show that in mammalian cells, PClP selectively inhibits myosin-1c function. To elucidate the structural basis for PClP-induced allosteric coupling and isoform-specific differences in the inhibitory potency of the compound, we used a multifaceted approach combining direct functional, crystallographic, and in silico modeling studies. Our results indicate that allosteric inhibition by PClP is mediated by the combined effects of global changes in protein dynamics and direct communication between the catalytic and allosteric sites via a cascade of small conformational changes along a conserved communication pathway.","downloadable_attachments":[{"id":46820786,"asset_id":26524407,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":14158350,"first_name":"Dietmar","last_name":"Manstein","domain_name":"mh-hannover","page_name":"DietmarManstein","display_name":"Dietmar Manstein","profile_url":"https://mh-hannover.academia.edu/DietmarManstein?f_ri=1970697","photo":"https://0.academia-photos.com/14158350/3891000/14578053/s65_dietmar.manstein.jpg"}],"research_interests":[{"id":18520,"name":"Biological Chemistry","url":"https://www.academia.edu/Documents/in/Biological_Chemistry?f_ri=1970697","nofollow":true},{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true},{"id":170274,"name":"Dictyostelium","url":"https://www.academia.edu/Documents/in/Dictyostelium?f_ri=1970697","nofollow":true},{"id":260118,"name":"CHEMICAL SCIENCES","url":"https://www.academia.edu/Documents/in/CHEMICAL_SCIENCES?f_ri=1970697","nofollow":true},{"id":375054,"name":"Rats","url":"https://www.academia.edu/Documents/in/Rats?f_ri=1970697"},{"id":402759,"name":"Chickens","url":"https://www.academia.edu/Documents/in/Chickens?f_ri=1970697"},{"id":788677,"name":"Rabbits","url":"https://www.academia.edu/Documents/in/Rabbits?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_20089883 coauthored" data-work_id="20089883" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/20089883/Centrally_Active_Allosteric_Potentiators_of_the_M4_Muscarinic_Acetylcholine_Receptor_Reverse_Amphetamine_Induced_Hyperlocomotor_Activity_in_Rats">Centrally Active Allosteric Potentiators of the M4 Muscarinic Acetylcholine Receptor Reverse Amphetamine-Induced Hyperlocomotor Activity in Rats</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">Previous clinical and animal studies suggest that selective activators of M 1 and/or M 4 muscarinic acetylcholine receptors (mAChRs) have potential as novel therapeutic agents for treatment of schizophrenia and Alzheimer's disease.... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_20089883" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">Previous clinical and animal studies suggest that selective activators of M 1 and/or M 4 muscarinic acetylcholine receptors (mAChRs) have potential as novel therapeutic agents for treatment of schizophrenia and Alzheimer's disease. However, highly selective centrally penetrant activators of either M 1 or M 4 have not been available, making it impossible to determine the in vivo effects of selective activation of these receptors. We previously identified VU10010 [3-amino-N-(4chlorobenzyl)-4, 6-dimethylthieno[2,3-b]pyridine-2-carboxamide] as a potent and selective allosteric potentiator of M 4 mAChRs. However, unfavorable physiochemical properties prevented use of this compound for in vivo studies. We now report that chemical optimization of VU10010 has afforded two centrally penetrant analogs, VU0152099 [3-amino-N-(benzo[d][1,3]dioxol-5ylmethyl)-4,6-dimethylthieno[2,3-b]pyridine carboxamide] and VU0152100 [3-amino-N-(4methoxybenzyl)-4,6-dimethylthieno[2,3-b]pyridine carboxamide], that are potent and selective positive allosteric modulators of M 4 . VU0152099 and VU0152100 had no agonist activity but potentiated responses of M 4 to acetylcholine. Both compounds were devoid of activity at other mAChR subtypes or at a panel of other GPCRs. The improved physiochemical properties of VU0152099 and VU0152100 allowed in vivo dosing and evaluation of behavioral effects in rats. Interestingly, these selective allosteric potentiators of M 4 reverse amphetamine-induced hyperlocomotion in rats, a model that is sensitive to known antipsychotic agents and to nonselective mAChR agonists. This is consistent with the hypothesis that M 4 plays an important role in regulating midbrain dopaminergic activity and raises the possibility that positive allosteric modulation of M 4 may mimic some of the antipsychotic-like effects of less selective mAChR agonists.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/20089883" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="e534d8868fa0829b101ba274d261af6b" rel="nofollow" data-download="{"attachment_id":41247933,"asset_id":20089883,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/41247933/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="41104696" href="https://sibs.academia.edu/HuiyongYin">Huiyong Yin</a><script data-card-contents-for-user="41104696" type="text/json">{"id":41104696,"first_name":"Huiyong","last_name":"Yin","domain_name":"sibs","page_name":"HuiyongYin","display_name":"Huiyong Yin","profile_url":"https://sibs.academia.edu/HuiyongYin?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span><span class="u-displayInlineBlock InlineList-item-text"> and <span class="u-textDecorationUnderline u-clickable InlineList-item-text js-work-more-authors-20089883">+1</span><div class="hidden js-additional-users-20089883"><div><span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a rel="nofollow" href="https://independent.academia.edu/ABrady1">A. 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However, highly selective centrally penetrant activators of either M 1 or M 4 have not been available, making it impossible to determine the in vivo effects of selective activation of these receptors. We previously identified VU10010 [3-amino-N-(4chlorobenzyl)-4, 6-dimethylthieno[2,3-b]pyridine-2-carboxamide] as a potent and selective allosteric potentiator of M 4 mAChRs. However, unfavorable physiochemical properties prevented use of this compound for in vivo studies. We now report that chemical optimization of VU10010 has afforded two centrally penetrant analogs, VU0152099 [3-amino-N-(benzo[d][1,3]dioxol-5ylmethyl)-4,6-dimethylthieno[2,3-b]pyridine carboxamide] and VU0152100 [3-amino-N-(4methoxybenzyl)-4,6-dimethylthieno[2,3-b]pyridine carboxamide], that are potent and selective positive allosteric modulators of M 4 . VU0152099 and VU0152100 had no agonist activity but potentiated responses of M 4 to acetylcholine. Both compounds were devoid of activity at other mAChR subtypes or at a panel of other GPCRs. The improved physiochemical properties of VU0152099 and VU0152100 allowed in vivo dosing and evaluation of behavioral effects in rats. Interestingly, these selective allosteric potentiators of M 4 reverse amphetamine-induced hyperlocomotion in rats, a model that is sensitive to known antipsychotic agents and to nonselective mAChR agonists. This is consistent with the hypothesis that M 4 plays an important role in regulating midbrain dopaminergic activity and raises the possibility that positive allosteric modulation of M 4 may mimic some of the antipsychotic-like effects of less selective mAChR agonists.","downloadable_attachments":[{"id":41247933,"asset_id":20089883,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":41104696,"first_name":"Huiyong","last_name":"Yin","domain_name":"sibs","page_name":"HuiyongYin","display_name":"Huiyong Yin","profile_url":"https://sibs.academia.edu/HuiyongYin?f_ri=1970697","photo":"/images/s65_no_pic.png"},{"id":41415787,"first_name":"A.","last_name":"Brady","domain_name":"independent","page_name":"ABrady1","display_name":"A. Brady","profile_url":"https://independent.academia.edu/ABrady1?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":140,"name":"Pharmacology","url":"https://www.academia.edu/Documents/in/Pharmacology?f_ri=1970697","nofollow":true},{"id":51566,"name":"Dopamine","url":"https://www.academia.edu/Documents/in/Dopamine?f_ri=1970697","nofollow":true},{"id":159958,"name":"Acetylcholine","url":"https://www.academia.edu/Documents/in/Acetylcholine?f_ri=1970697","nofollow":true},{"id":375054,"name":"Rats","url":"https://www.academia.edu/Documents/in/Rats?f_ri=1970697","nofollow":true},{"id":490260,"name":"Pyridines","url":"https://www.academia.edu/Documents/in/Pyridines?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"},{"id":2246318,"name":"Motor activity","url":"https://www.academia.edu/Documents/in/Motor_activity?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_11718449" data-work_id="11718449" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/11718449/Molecular_Interactions_between_Mecamylamine_Enantiomers_and_the_Transmembrane_Domain_of_the_Human_%CE%B14%CE%B22_Nicotinic_Receptor">Molecular Interactions between Mecamylamine Enantiomers and the Transmembrane Domain of the Human α4β2 Nicotinic Receptor</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">To characterize the binding sites of mecamylamine enantiomers on the transmembrane domain (TMD) of human (h) (α4) 3 (β2) 2 and (α4) 2 (β2) 3 nicotinic acetylcholine receptors (AChRs), we used nuclear magnetic resonance (NMR), molecular... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_11718449" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">To characterize the binding sites of mecamylamine enantiomers on the transmembrane domain (TMD) of human (h) (α4) 3 (β2) 2 and (α4) 2 (β2) 3 nicotinic acetylcholine receptors (AChRs), we used nuclear magnetic resonance (NMR), molecular docking, and radioligand binding approaches. The interactions of (S)-(+)-and (R)-(−)-mecamylamine with several residues, determined by high-resolution NMR, within the hα4β2-TMD indicate different modes of binding at several luminal (L) and nonluminal (NL) sites. In general, the residues sensitive to each mecamylamine enantiomer are similar at both receptor stoichiometries. However, some differences were observed. The molecular docking experiments were crucial for delineating the location and orientation of each enantiomer in its binding site. In the (α4) 2 (β2) 3 -TMD, (S)-(+)-mecamylamine interacts with the L1 (i.e., between positions −3′ and −5′) and L2 (i.e., between positions 16′ and 20′) sites, whereas the β2-intersubunit (i.e., cytoplasmic end of two β2-TMDs) and α4/β2-intersubunit (i.e., cytoplasmic end of α4-TM1 and β2-TM3) sites are shared by both enantiomers. In the (α4) 3 (β2) 2 -TMD, both enantiomers bind with different orientations to the L1′ (closer to ring 2′) and α4-intrasubunit (i.e., at the cytoplasmic ends of α4-TM1 and α4-TM2) sites, but only (R)-(−)-mecamylamine interacts with the L2′ (i.e., closer to ring 20′) and α4-TM3-intrasubunit sites. Our findings are important because they provide, for the first time, a structural understanding of the allosteric modulation elicited by mecamylamine enantiomers at each hα4β2 stoichiometry. This advancement could be beneficial for the development of novel therapies for the treatment of several neurological disorders.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/11718449" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="76f5c4465fb99f350203f28e40ed6e3c" rel="nofollow" data-download="{"attachment_id":46559857,"asset_id":11718449,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/46559857/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="28736965" href="https://independent.academia.edu/KatarzynaTargowskaduda">Katarzyna Targowska-duda</a><script data-card-contents-for-user="28736965" type="text/json">{"id":28736965,"first_name":"Katarzyna","last_name":"Targowska-duda","domain_name":"independent","page_name":"KatarzynaTargowskaduda","display_name":"Katarzyna Targowska-duda","profile_url":"https://independent.academia.edu/KatarzynaTargowskaduda?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_11718449 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="11718449"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 11718449, container: ".js-paper-rank-work_11718449", }); });</script></li><li class="js-percentile-work_11718449 InlineList-item InlineList-item--bordered hidden u-tcGrayDark"><span class="percentile-widget hidden"><span class="u-mr2x percentile-widget" style="display: none">•</span><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 11718449; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-percentile-work_11718449"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></li><li class="js-view-count-work_11718449 InlineList-item InlineList-item--bordered hidden"><div><span><span class="js-view-count view-count u-mr2x" data-work-id="11718449"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 11718449; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=11718449]").text(description); $(".js-view-count-work_11718449").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_11718449").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="11718449"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">6</a>  </div><span class="InlineList-item-text u-textTruncate u-pl9x"><a class="InlineList-item-text" data-has-card-for-ri="145" rel="nofollow" href="https://www.academia.edu/Documents/in/Biochemistry">Biochemistry</a>, <script data-card-contents-for-ri="145" type="text/json">{"id":145,"name":"Biochemistry","url":"https://www.academia.edu/Documents/in/Biochemistry?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="21732" rel="nofollow" href="https://www.academia.edu/Documents/in/Magnetic_Resonance_Spectroscopy">Magnetic Resonance Spectroscopy</a>, <script data-card-contents-for-ri="21732" type="text/json">{"id":21732,"name":"Magnetic Resonance Spectroscopy","url":"https://www.academia.edu/Documents/in/Magnetic_Resonance_Spectroscopy?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="125691" rel="nofollow" href="https://www.academia.edu/Documents/in/Nicotinic_Acetylcholine_Receptors">Nicotinic Acetylcholine Receptors</a>, <script data-card-contents-for-ri="125691" type="text/json">{"id":125691,"name":"Nicotinic Acetylcholine Receptors","url":"https://www.academia.edu/Documents/in/Nicotinic_Acetylcholine_Receptors?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="740505" rel="nofollow" href="https://www.academia.edu/Documents/in/Mecamylamine">Mecamylamine</a><script data-card-contents-for-ri="740505" type="text/json">{"id":740505,"name":"Mecamylamine","url":"https://www.academia.edu/Documents/in/Mecamylamine?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=11718449]'), work: {"id":11718449,"title":"Molecular Interactions between Mecamylamine Enantiomers and the Transmembrane Domain of the Human α4β2 Nicotinic Receptor","created_at":"2015-03-30T03:53:44.059-07:00","url":"https://www.academia.edu/11718449/Molecular_Interactions_between_Mecamylamine_Enantiomers_and_the_Transmembrane_Domain_of_the_Human_%CE%B14%CE%B22_Nicotinic_Receptor?f_ri=1970697","dom_id":"work_11718449","summary":"To characterize the binding sites of mecamylamine enantiomers on the transmembrane domain (TMD) of human (h) (α4) 3 (β2) 2 and (α4) 2 (β2) 3 nicotinic acetylcholine receptors (AChRs), we used nuclear magnetic resonance (NMR), molecular docking, and radioligand binding approaches. The interactions of (S)-(+)-and (R)-(−)-mecamylamine with several residues, determined by high-resolution NMR, within the hα4β2-TMD indicate different modes of binding at several luminal (L) and nonluminal (NL) sites. In general, the residues sensitive to each mecamylamine enantiomer are similar at both receptor stoichiometries. However, some differences were observed. The molecular docking experiments were crucial for delineating the location and orientation of each enantiomer in its binding site. In the (α4) 2 (β2) 3 -TMD, (S)-(+)-mecamylamine interacts with the L1 (i.e., between positions −3′ and −5′) and L2 (i.e., between positions 16′ and 20′) sites, whereas the β2-intersubunit (i.e., cytoplasmic end of two β2-TMDs) and α4/β2-intersubunit (i.e., cytoplasmic end of α4-TM1 and β2-TM3) sites are shared by both enantiomers. In the (α4) 3 (β2) 2 -TMD, both enantiomers bind with different orientations to the L1′ (closer to ring 2′) and α4-intrasubunit (i.e., at the cytoplasmic ends of α4-TM1 and α4-TM2) sites, but only (R)-(−)-mecamylamine interacts with the L2′ (i.e., closer to ring 20′) and α4-TM3-intrasubunit sites. Our findings are important because they provide, for the first time, a structural understanding of the allosteric modulation elicited by mecamylamine enantiomers at each hα4β2 stoichiometry. This advancement could be beneficial for the development of novel therapies for the treatment of several neurological disorders.","downloadable_attachments":[{"id":46559857,"asset_id":11718449,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":28736965,"first_name":"Katarzyna","last_name":"Targowska-duda","domain_name":"independent","page_name":"KatarzynaTargowskaduda","display_name":"Katarzyna Targowska-duda","profile_url":"https://independent.academia.edu/KatarzynaTargowskaduda?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":145,"name":"Biochemistry","url":"https://www.academia.edu/Documents/in/Biochemistry?f_ri=1970697","nofollow":true},{"id":21732,"name":"Magnetic Resonance Spectroscopy","url":"https://www.academia.edu/Documents/in/Magnetic_Resonance_Spectroscopy?f_ri=1970697","nofollow":true},{"id":125691,"name":"Nicotinic Acetylcholine Receptors","url":"https://www.academia.edu/Documents/in/Nicotinic_Acetylcholine_Receptors?f_ri=1970697","nofollow":true},{"id":740505,"name":"Mecamylamine","url":"https://www.academia.edu/Documents/in/Mecamylamine?f_ri=1970697","nofollow":true},{"id":1681026,"name":"Biochemistry and cell biology","url":"https://www.academia.edu/Documents/in/Biochemistry_and_cell_biology?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_14860073" data-work_id="14860073" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/14860073/Enzyme_Activity_Control">Enzyme Activity: Control</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest">Enzymes are the metabolic catalysts that effect a multitude of physiological processes and responses. Tight control of enzyme activity is therefore essential in maintaining the steady state of all organisms.</div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/14860073" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="dc9e9e4ad02c966f35fcd3c6fd245b4c" rel="nofollow" data-download="{"attachment_id":43836879,"asset_id":14860073,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/43836879/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="33832322" href="https://independent.academia.edu/GeorgeChaoJiang">George Chao Jiang</a><script data-card-contents-for-user="33832322" type="text/json">{"id":33832322,"first_name":"George Chao","last_name":"Jiang","domain_name":"independent","page_name":"GeorgeChaoJiang","display_name":"George Chao Jiang","profile_url":"https://independent.academia.edu/GeorgeChaoJiang?f_ri=1970697","photo":"https://0.academia-photos.com/33832322/10690346/11934378/s65_george_chao.jiang.jpg_oh_32af708777d6b6004d15fd2da945fc49_oe_56e83485"}</script></span></span></li><li class="js-paper-rank-work_14860073 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="14860073"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 14860073, container: ".js-paper-rank-work_14860073", }); });</script></li><li class="js-percentile-work_14860073 InlineList-item InlineList-item--bordered hidden u-tcGrayDark"><span class="percentile-widget hidden"><span class="u-mr2x percentile-widget" style="display: none">•</span><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 14860073; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-percentile-work_14860073"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></li><li class="js-view-count-work_14860073 InlineList-item InlineList-item--bordered hidden"><div><span><span class="js-view-count view-count u-mr2x" data-work-id="14860073"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 14860073; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=14860073]").text(description); $(".js-view-count-work_14860073").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_14860073").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="14860073"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">2</a>  </div><span class="InlineList-item-text u-textTruncate u-pl9x"><a class="InlineList-item-text" data-has-card-for-ri="172083" rel="nofollow" href="https://www.academia.edu/Documents/in/Phosphorylation">Phosphorylation</a>, <script data-card-contents-for-ri="172083" type="text/json">{"id":172083,"name":"Phosphorylation","url":"https://www.academia.edu/Documents/in/Phosphorylation?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="1970697" rel="nofollow" href="https://www.academia.edu/Documents/in/Allosteric_regulation">Allosteric regulation</a><script data-card-contents-for-ri="1970697" type="text/json">{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=14860073]'), work: {"id":14860073,"title":"Enzyme Activity: Control","created_at":"2015-08-11T18:07:10.640-07:00","url":"https://www.academia.edu/14860073/Enzyme_Activity_Control?f_ri=1970697","dom_id":"work_14860073","summary":"Enzymes are the metabolic catalysts that effect a multitude of physiological processes and responses. Tight control of enzyme activity is therefore essential in maintaining the steady state of all organisms.","downloadable_attachments":[{"id":43836879,"asset_id":14860073,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":33832322,"first_name":"George Chao","last_name":"Jiang","domain_name":"independent","page_name":"GeorgeChaoJiang","display_name":"George Chao Jiang","profile_url":"https://independent.academia.edu/GeorgeChaoJiang?f_ri=1970697","photo":"https://0.academia-photos.com/33832322/10690346/11934378/s65_george_chao.jiang.jpg_oh_32af708777d6b6004d15fd2da945fc49_oe_56e83485"}],"research_interests":[{"id":172083,"name":"Phosphorylation","url":"https://www.academia.edu/Documents/in/Phosphorylation?f_ri=1970697","nofollow":true},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697","nofollow":true}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_23723385 coauthored" data-work_id="23723385" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/23723385/The_water_effect_on_the_kinetic_of_the_bovine_liver_catalase">The water effect on the kinetic of the bovine liver catalase</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">Catalase is an enzyme that occurs in almost all aerobic organisms. Its main metabolic function is to prevent oxidative damage to tissues induced by hydrogen peroxide which is a strong oxidizing agent. Catalase is very effective in... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_23723385" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">Catalase is an enzyme that occurs in almost all aerobic organisms. Its main metabolic function is to prevent oxidative damage to tissues induced by hydrogen peroxide which is a strong oxidizing agent. Catalase is very effective in performing this task, since it has the highest turnover rate among all the enzymes. The properties of catalase have been investigated extensively for many years; however, the role of the solvent molecules in the catalytic reaction of this enzyme has not yet been investigated. Therefore, the objective of this work was to investigate the contribution of the solvent molecules on the catalytic reaction of bovine liver catalase with its substrate H2O2 by the osmotic stress method. As a probe for protein structural changes in solution, the differential number of water molecules released during the transition from free to bound form of the enzyme was measured. These assays were correlated with protein structural data provided by the SAXS technique and crystallogr...</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/23723385" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="95de06534b9e1ef0c5eef594aa9453f3" rel="nofollow" data-download="{"attachment_id":44150913,"asset_id":23723385,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/44150913/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="46607244" href="https://maringa.academia.edu/FlavioSeixas">Flavio Seixas</a><script data-card-contents-for-user="46607244" type="text/json">{"id":46607244,"first_name":"Flavio","last_name":"Seixas","domain_name":"maringa","page_name":"FlavioSeixas","display_name":"Flavio Seixas","profile_url":"https://maringa.academia.edu/FlavioSeixas?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span><span class="u-displayInlineBlock InlineList-item-text"> and <span class="u-textDecorationUnderline u-clickable InlineList-item-text js-work-more-authors-23723385">+1</span><div class="hidden js-additional-users-23723385"><div><span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a href="https://unesp.academia.edu/MarcioColombo">Marcio F Colombo</a></span></div></div></span><script>(function(){ var popoverSettings = { el: $('.js-work-more-authors-23723385'), placement: 'bottom', hide_delay: 200, html: true, content: function(){ return $('.js-additional-users-23723385').html(); } } new HoverPopover(popoverSettings); })();</script></li><li class="js-paper-rank-work_23723385 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="23723385"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 23723385, container: ".js-paper-rank-work_23723385", }); });</script></li><li class="js-percentile-work_23723385 InlineList-item InlineList-item--bordered hidden u-tcGrayDark"><span class="percentile-widget hidden"><span class="u-mr2x percentile-widget" style="display: none">•</span><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 23723385; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-percentile-work_23723385"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></li><li class="js-view-count-work_23723385 InlineList-item InlineList-item--bordered hidden"><div><span><span class="js-view-count view-count u-mr2x" data-work-id="23723385"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 23723385; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=23723385]").text(description); $(".js-view-count-work_23723385").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_23723385").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="23723385"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">9</a>  </div><span class="InlineList-item-text u-textTruncate u-pl9x"><a class="InlineList-item-text" data-has-card-for-ri="2215" rel="nofollow" href="https://www.academia.edu/Documents/in/Water">Water</a>, <script data-card-contents-for-ri="2215" type="text/json">{"id":2215,"name":"Water","url":"https://www.academia.edu/Documents/in/Water?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="4987" rel="nofollow" href="https://www.academia.edu/Documents/in/Kinetics">Kinetics</a>, <script data-card-contents-for-ri="4987" type="text/json">{"id":4987,"name":"Kinetics","url":"https://www.academia.edu/Documents/in/Kinetics?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="71437" rel="nofollow" href="https://www.academia.edu/Documents/in/Liver">Liver</a>, <script data-card-contents-for-ri="71437" type="text/json">{"id":71437,"name":"Liver","url":"https://www.academia.edu/Documents/in/Liver?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="133362" rel="nofollow" href="https://www.academia.edu/Documents/in/Osmotic_pressure">Osmotic pressure</a><script data-card-contents-for-ri="133362" type="text/json">{"id":133362,"name":"Osmotic pressure","url":"https://www.academia.edu/Documents/in/Osmotic_pressure?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=23723385]'), work: {"id":23723385,"title":"The water effect on the kinetic of the bovine liver catalase","created_at":"2016-03-27T14:51:16.102-07:00","url":"https://www.academia.edu/23723385/The_water_effect_on_the_kinetic_of_the_bovine_liver_catalase?f_ri=1970697","dom_id":"work_23723385","summary":"Catalase is an enzyme that occurs in almost all aerobic organisms. Its main metabolic function is to prevent oxidative damage to tissues induced by hydrogen peroxide which is a strong oxidizing agent. Catalase is very effective in performing this task, since it has the highest turnover rate among all the enzymes. The properties of catalase have been investigated extensively for many years; however, the role of the solvent molecules in the catalytic reaction of this enzyme has not yet been investigated. Therefore, the objective of this work was to investigate the contribution of the solvent molecules on the catalytic reaction of bovine liver catalase with its substrate H2O2 by the osmotic stress method. As a probe for protein structural changes in solution, the differential number of water molecules released during the transition from free to bound form of the enzyme was measured. These assays were correlated with protein structural data provided by the SAXS technique and crystallogr...","downloadable_attachments":[{"id":44150913,"asset_id":23723385,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":46607244,"first_name":"Flavio","last_name":"Seixas","domain_name":"maringa","page_name":"FlavioSeixas","display_name":"Flavio Seixas","profile_url":"https://maringa.academia.edu/FlavioSeixas?f_ri=1970697","photo":"/images/s65_no_pic.png"},{"id":9015808,"first_name":"Marcio","last_name":"Colombo","domain_name":"unesp","page_name":"MarcioColombo","display_name":"Marcio F Colombo","profile_url":"https://unesp.academia.edu/MarcioColombo?f_ri=1970697","photo":"https://0.academia-photos.com/9015808/28137728/26358173/s65_marcio.colombo.jpg"}],"research_interests":[{"id":2215,"name":"Water","url":"https://www.academia.edu/Documents/in/Water?f_ri=1970697","nofollow":true},{"id":4987,"name":"Kinetics","url":"https://www.academia.edu/Documents/in/Kinetics?f_ri=1970697","nofollow":true},{"id":71437,"name":"Liver","url":"https://www.academia.edu/Documents/in/Liver?f_ri=1970697","nofollow":true},{"id":133362,"name":"Osmotic pressure","url":"https://www.academia.edu/Documents/in/Osmotic_pressure?f_ri=1970697","nofollow":true},{"id":139007,"name":"Catalase","url":"https://www.academia.edu/Documents/in/Catalase?f_ri=1970697"},{"id":260829,"name":"Cattle","url":"https://www.academia.edu/Documents/in/Cattle?f_ri=1970697"},{"id":274826,"name":"Hydrogen Peroxide","url":"https://www.academia.edu/Documents/in/Hydrogen_Peroxide?f_ri=1970697"},{"id":1681026,"name":"Biochemistry and cell biology","url":"https://www.academia.edu/Documents/in/Biochemistry_and_cell_biology?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_54171463" data-work_id="54171463" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/54171463/A_new_mechanism_of_allostery_in_a_G_protein_coupled_receptor_dimer">A new mechanism of allostery in a G protein–coupled receptor dimer</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">SB269652 (1) is the first drug-like allosteric modulator of the dopamine D 2 receptor (D 2 R), but contains structural features associated with orthosteric D 2 R antagonists. Using a functional complementation system to control the... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_54171463" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">SB269652 (1) is the first drug-like allosteric modulator of the dopamine D 2 receptor (D 2 R), but contains structural features associated with orthosteric D 2 R antagonists. Using a functional complementation system to control the identity of individual protomers within a dimeric D 2 R complex, we converted the pharmacology of the interaction between SB269652 and dopamine Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/54171463" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="84aa569990d33309eb7bd943aadeff64" rel="nofollow" data-download="{"attachment_id":70665032,"asset_id":54171463,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/70665032/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="32593836" href="https://independent.academia.edu/BenCapuano">Ben Capuano</a><script data-card-contents-for-user="32593836" type="text/json">{"id":32593836,"first_name":"Ben","last_name":"Capuano","domain_name":"independent","page_name":"BenCapuano","display_name":"Ben Capuano","profile_url":"https://independent.academia.edu/BenCapuano?f_ri=1970697","photo":"https://0.academia-photos.com/32593836/161336025/151056940/s65_ben.capuano.png"}</script></span></span></li><li class="js-paper-rank-work_54171463 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="54171463"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 54171463, container: ".js-paper-rank-work_54171463", }); });</script></li><li class="js-percentile-work_54171463 InlineList-item InlineList-item--bordered hidden u-tcGrayDark"><span class="percentile-widget hidden"><span class="u-mr2x percentile-widget" style="display: none">•</span><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 54171463; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-percentile-work_54171463"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></li><li class="js-view-count-work_54171463 InlineList-item InlineList-item--bordered hidden"><div><span><span class="js-view-count view-count u-mr2x" data-work-id="54171463"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 54171463; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=54171463]").text(description); $(".js-view-count-work_54171463").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_54171463").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="54171463"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">11</a>  </div><span class="InlineList-item-text u-textTruncate u-pl10x"><a class="InlineList-item-text" data-has-card-for-ri="140" rel="nofollow" href="https://www.academia.edu/Documents/in/Pharmacology">Pharmacology</a>, <script data-card-contents-for-ri="140" type="text/json">{"id":140,"name":"Pharmacology","url":"https://www.academia.edu/Documents/in/Pharmacology?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="38831" rel="nofollow" href="https://www.academia.edu/Documents/in/Signal_Transduction">Signal Transduction</a>, <script data-card-contents-for-ri="38831" type="text/json">{"id":38831,"name":"Signal Transduction","url":"https://www.academia.edu/Documents/in/Signal_Transduction?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="86313" rel="nofollow" href="https://www.academia.edu/Documents/in/G_protein-coupled_receptors">G protein-coupled receptors</a>, <script data-card-contents-for-ri="86313" type="text/json">{"id":86313,"name":"G protein-coupled receptors","url":"https://www.academia.edu/Documents/in/G_protein-coupled_receptors?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="375054" rel="nofollow" href="https://www.academia.edu/Documents/in/Rats">Rats</a><script data-card-contents-for-ri="375054" type="text/json">{"id":375054,"name":"Rats","url":"https://www.academia.edu/Documents/in/Rats?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=54171463]'), work: {"id":54171463,"title":"A new mechanism of allostery in a G protein–coupled receptor dimer","created_at":"2021-09-30T00:02:49.026-07:00","url":"https://www.academia.edu/54171463/A_new_mechanism_of_allostery_in_a_G_protein_coupled_receptor_dimer?f_ri=1970697","dom_id":"work_54171463","summary":"SB269652 (1) is the first drug-like allosteric modulator of the dopamine D 2 receptor (D 2 R), but contains structural features associated with orthosteric D 2 R antagonists. Using a functional complementation system to control the identity of individual protomers within a dimeric D 2 R complex, we converted the pharmacology of the interaction between SB269652 and dopamine Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:","downloadable_attachments":[{"id":70665032,"asset_id":54171463,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":32593836,"first_name":"Ben","last_name":"Capuano","domain_name":"independent","page_name":"BenCapuano","display_name":"Ben Capuano","profile_url":"https://independent.academia.edu/BenCapuano?f_ri=1970697","photo":"https://0.academia-photos.com/32593836/161336025/151056940/s65_ben.capuano.png"}],"research_interests":[{"id":140,"name":"Pharmacology","url":"https://www.academia.edu/Documents/in/Pharmacology?f_ri=1970697","nofollow":true},{"id":38831,"name":"Signal Transduction","url":"https://www.academia.edu/Documents/in/Signal_Transduction?f_ri=1970697","nofollow":true},{"id":86313,"name":"G protein-coupled receptors","url":"https://www.academia.edu/Documents/in/G_protein-coupled_receptors?f_ri=1970697","nofollow":true},{"id":375054,"name":"Rats","url":"https://www.academia.edu/Documents/in/Rats?f_ri=1970697","nofollow":true},{"id":653665,"name":"Protein Conformation","url":"https://www.academia.edu/Documents/in/Protein_Conformation?f_ri=1970697"},{"id":1222191,"name":"Ligands","url":"https://www.academia.edu/Documents/in/Ligands?f_ri=1970697"},{"id":1457054,"name":"Protein Transport","url":"https://www.academia.edu/Documents/in/Protein_Transport?f_ri=1970697"},{"id":1681026,"name":"Biochemistry and cell biology","url":"https://www.academia.edu/Documents/in/Biochemistry_and_cell_biology?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"},{"id":2898895,"name":"binding sites","url":"https://www.academia.edu/Documents/in/binding_sites?f_ri=1970697"},{"id":3384699,"name":"G Protein Coupled Receptors","url":"https://www.academia.edu/Documents/in/G_Protein_Coupled_Receptors?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_18109807" data-work_id="18109807" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/18109807/Allosteric_Models_for_Multimeric_Proteins_Oxygen_Linked_Effector_Binding_in_Hemocyanin_">Allosteric Models for Multimeric Proteins: Oxygen-Linked Effector Binding in Hemocyanin †</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">In many crustaceans, changing concentrations of several low molecular weight compounds modulates hemocyanin oxygen binding, resulting in lower or higher oxygen affinities of the pigment. The nonphysiological effector caffeine and the... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_18109807" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">In many crustaceans, changing concentrations of several low molecular weight compounds modulates hemocyanin oxygen binding, resulting in lower or higher oxygen affinities of the pigment. The nonphysiological effector caffeine and the physiological modulator urate, the latter accumulating in the hemolymph of the lobster Homarus Vulgaris during hypoxia, increase hemocyanin oxygen affinity and decrease cooperativity of oxygen binding. To derive a model that describes the mechanism of allosteric interaction between hemocyanin and oxygen in the presence of urate or caffeine, studies of oxygen, urate, and caffeine binding to hemocyanin were performed. Exposure of lobster hemocyanin to various pH values between 7.25 and 8.15 resulted in a decrease of p50. In this pH interval, p50 decreases from 95 to 11 Torr without effectors and from 49 to 6 Torr and from 34 to 5 Torr in the presence of 1 mM urate or caffeine, respectively. Thus, the allosteric effects induced by protons and urate or caffeine are coupled. In contrast, isothermal titration calorimetry did not reveal any differences in binding enthalpy (∆H°) for urate or caffeine under either normoxic or hypoxic conditions at different pH values. Despite these apparently conflicting results, they can be explained by the nested MWC model if two different types of modulator binding sites are assumed, an allosteric and a nonallosteric type of site. Simulations of in ViVo conditions with this model indicate that the naturally occurring modulator urate is physiologically relevant in H. Vulgaris only during hypoxic conditions, i.e., either during environmental oxygen limitation or extensive exercise.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/18109807" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="4e95cba4f3a0c1eeb897432215342b8f" rel="nofollow" data-download="{"attachment_id":39880359,"asset_id":18109807,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/39880359/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="38061021" href="https://uni-mainz.academia.edu/HeinzDecker">Heinz Decker</a><script data-card-contents-for-user="38061021" type="text/json">{"id":38061021,"first_name":"Heinz","last_name":"Decker","domain_name":"uni-mainz","page_name":"HeinzDecker","display_name":"Heinz Decker","profile_url":"https://uni-mainz.academia.edu/HeinzDecker?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_18109807 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="18109807"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 18109807, container: ".js-paper-rank-work_18109807", }); 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The nonphysiological effector caffeine and the physiological modulator urate, the latter accumulating in the hemolymph of the lobster Homarus Vulgaris during hypoxia, increase hemocyanin oxygen affinity and decrease cooperativity of oxygen binding. To derive a model that describes the mechanism of allosteric interaction between hemocyanin and oxygen in the presence of urate or caffeine, studies of oxygen, urate, and caffeine binding to hemocyanin were performed. Exposure of lobster hemocyanin to various pH values between 7.25 and 8.15 resulted in a decrease of p50. In this pH interval, p50 decreases from 95 to 11 Torr without effectors and from 49 to 6 Torr and from 34 to 5 Torr in the presence of 1 mM urate or caffeine, respectively. Thus, the allosteric effects induced by protons and urate or caffeine are coupled. In contrast, isothermal titration calorimetry did not reveal any differences in binding enthalpy (∆H°) for urate or caffeine under either normoxic or hypoxic conditions at different pH values. Despite these apparently conflicting results, they can be explained by the nested MWC model if two different types of modulator binding sites are assumed, an allosteric and a nonallosteric type of site. Simulations of in ViVo conditions with this model indicate that the naturally occurring modulator urate is physiologically relevant in H. Vulgaris only during hypoxic conditions, i.e., either during environmental oxygen limitation or extensive exercise.","downloadable_attachments":[{"id":39880359,"asset_id":18109807,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":38061021,"first_name":"Heinz","last_name":"Decker","domain_name":"uni-mainz","page_name":"HeinzDecker","display_name":"Heinz Decker","profile_url":"https://uni-mainz.academia.edu/HeinzDecker?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":145,"name":"Biochemistry","url":"https://www.academia.edu/Documents/in/Biochemistry?f_ri=1970697","nofollow":true},{"id":67129,"name":"Caffeine","url":"https://www.academia.edu/Documents/in/Caffeine?f_ri=1970697","nofollow":true},{"id":67133,"name":"Anoxia","url":"https://www.academia.edu/Documents/in/Anoxia?f_ri=1970697","nofollow":true},{"id":309088,"name":"Uric Acid","url":"https://www.academia.edu/Documents/in/Uric_Acid?f_ri=1970697","nofollow":true},{"id":380825,"name":"Oxygen","url":"https://www.academia.edu/Documents/in/Oxygen?f_ri=1970697"},{"id":651659,"name":"Isothermal Titration Calorimetry","url":"https://www.academia.edu/Documents/in/Isothermal_Titration_Calorimetry?f_ri=1970697"},{"id":653665,"name":"Protein Conformation","url":"https://www.academia.edu/Documents/in/Protein_Conformation?f_ri=1970697"},{"id":677739,"name":"Calorimetry","url":"https://www.academia.edu/Documents/in/Calorimetry?f_ri=1970697"},{"id":1010725,"name":"Protein Binding","url":"https://www.academia.edu/Documents/in/Protein_Binding?f_ri=1970697"},{"id":1242506,"name":"Binding Site","url":"https://www.academia.edu/Documents/in/Binding_Site?f_ri=1970697"},{"id":1496706,"name":"Low molecular weight","url":"https://www.academia.edu/Documents/in/Low_molecular_weight?f_ri=1970697"},{"id":1681026,"name":"Biochemistry and cell biology","url":"https://www.academia.edu/Documents/in/Biochemistry_and_cell_biology?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_51162815" data-work_id="51162815" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/51162815/Nonhierarchical_Flux_Regulation_Exposes_the_Fitness_Burden_Associated_with_Lactate_Production_in_Synechocystis_sp_PCC6803">Nonhierarchical Flux Regulation Exposes the Fitness Burden Associated with Lactate Production in Synechocystis sp. PCC6803</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">Cyanobacteria are mostly engineered to be sustainable cell-factories by genetic manipulations alone. Here, by modulating the concentration of allosteric effectors, we focus on increasing product formation without further burdening the... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_51162815" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">Cyanobacteria are mostly engineered to be sustainable cell-factories by genetic manipulations alone. Here, by modulating the concentration of allosteric effectors, we focus on increasing product formation without further burdening the cells with increased expression of enzymes. Resorting to a novel 96-well microplate cultivation system for cyanobacteria, and using lactate-producing strains of Synechocystis PCC6803 expressing different l-lactate dehydrogenases (LDH), we titrated the effect of 2,5-anhydro-mannitol supplementation. The latter acts in cells as a nonmetabolizable analogue of fructose 1,6-bisphosphate, a known allosteric regulator of one of the tested LDHs. In this strain (SAA023), we achieved over 2-fold increase of lactate productivity. Furthermore, we observed that as carbon is increasingly deviated during growth toward product formation, there is an increased fixation rate in the population of spontaneous mutants harboring an impaired production pathway. This is a cha...</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/51162815" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="df6ab71bab640715343137cb95aa797f" rel="nofollow" data-download="{"attachment_id":68998778,"asset_id":51162815,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/68998778/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="31900435" href="https://independent.academia.edu/KlaasHellingwerf">Klaas Hellingwerf</a><script data-card-contents-for-user="31900435" type="text/json">{"id":31900435,"first_name":"Klaas","last_name":"Hellingwerf","domain_name":"independent","page_name":"KlaasHellingwerf","display_name":"Klaas Hellingwerf","profile_url":"https://independent.academia.edu/KlaasHellingwerf?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_51162815 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="51162815"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 51162815, container: ".js-paper-rank-work_51162815", }); 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PCC6803","created_at":"2021-09-02T12:24:24.003-07:00","url":"https://www.academia.edu/51162815/Nonhierarchical_Flux_Regulation_Exposes_the_Fitness_Burden_Associated_with_Lactate_Production_in_Synechocystis_sp_PCC6803?f_ri=1970697","dom_id":"work_51162815","summary":"Cyanobacteria are mostly engineered to be sustainable cell-factories by genetic manipulations alone. Here, by modulating the concentration of allosteric effectors, we focus on increasing product formation without further burdening the cells with increased expression of enzymes. Resorting to a novel 96-well microplate cultivation system for cyanobacteria, and using lactate-producing strains of Synechocystis PCC6803 expressing different l-lactate dehydrogenases (LDH), we titrated the effect of 2,5-anhydro-mannitol supplementation. The latter acts in cells as a nonmetabolizable analogue of fructose 1,6-bisphosphate, a known allosteric regulator of one of the tested LDHs. In this strain (SAA023), we achieved over 2-fold increase of lactate productivity. Furthermore, we observed that as carbon is increasingly deviated during growth toward product formation, there is an increased fixation rate in the population of spontaneous mutants harboring an impaired production pathway. This is a cha...","downloadable_attachments":[{"id":68998778,"asset_id":51162815,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":31900435,"first_name":"Klaas","last_name":"Hellingwerf","domain_name":"independent","page_name":"KlaasHellingwerf","display_name":"Klaas Hellingwerf","profile_url":"https://independent.academia.edu/KlaasHellingwerf?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":1074508,"name":"Lactic Acid","url":"https://www.academia.edu/Documents/in/Lactic_Acid?f_ri=1970697","nofollow":true},{"id":1703031,"name":"Mannitol","url":"https://www.academia.edu/Documents/in/Mannitol?f_ri=1970697","nofollow":true},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697","nofollow":true},{"id":3963566,"name":"Synechocystis","url":"https://www.academia.edu/Documents/in/Synechocystis?f_ri=1970697","nofollow":true}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_6984933" data-work_id="6984933" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/6984933/Electrostatic_Basis_for_Enzyme_Catalysis">Electrostatic Basis for Enzyme Catalysis</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest">ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. 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To access a ChemInform Abstract, please click on HTML or PDF.","downloadable_attachments":[{"id":48644789,"asset_id":6984933,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":11855985,"first_name":"Pankaz","last_name":"Sharma","domain_name":"independent","page_name":"SharmaPankaz","display_name":"Pankaz Sharma","profile_url":"https://independent.academia.edu/SharmaPankaz?f_ri=1970697","photo":"https://0.academia-photos.com/11855985/75304314/63813157/s65_pankaz.sharma.jpeg"}],"research_interests":[{"id":522,"name":"Thermodynamics","url":"https://www.academia.edu/Documents/in/Thermodynamics?f_ri=1970697","nofollow":true},{"id":4749,"name":"Catalysis","url":"https://www.academia.edu/Documents/in/Catalysis?f_ri=1970697","nofollow":true},{"id":6811,"name":"Quantum Theory","url":"https://www.academia.edu/Documents/in/Quantum_Theory?f_ri=1970697","nofollow":true},{"id":14054,"name":"Chemical","url":"https://www.academia.edu/Documents/in/Chemical?f_ri=1970697","nofollow":true},{"id":55163,"name":"Enzymes","url":"https://www.academia.edu/Documents/in/Enzymes?f_ri=1970697"},{"id":260118,"name":"CHEMICAL SCIENCES","url":"https://www.academia.edu/Documents/in/CHEMICAL_SCIENCES?f_ri=1970697"},{"id":1430488,"name":"Enzyme Catalysis","url":"https://www.academia.edu/Documents/in/Enzyme_Catalysis?f_ri=1970697"},{"id":1451660,"name":"Static Electricity","url":"https://www.academia.edu/Documents/in/Static_Electricity?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_3989615" data-work_id="3989615" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/3989615/Unusual_oxygen_binding_behavior_of_a_24_meric_crustacean_hemocyanin">Unusual oxygen binding behavior of a 24-meric crustacean hemocyanin</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">Hemocyanins from Crustacea usually are found as 1 × 6 or 2 × 6-meric assemblies. An exception is the hemocyanin isolated from thalassinidean shrimps where the main component is a 24-meric structure. Our analysis of oxygen binding data of... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_3989615" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">Hemocyanins from Crustacea usually are found as 1 × 6 or 2 × 6-meric assemblies. An exception is the hemocyanin isolated from thalassinidean shrimps where the main component is a 24-meric structure. Our analysis of oxygen binding data of the thalassinidean shrimp Upogebia pusilla based on a three-state MWC-model revealed that despite the 24-meric structure the functional properties can be described very well based on the hexamer as allosteric unit. In contrast to the hemocyanins from other thalassinidean shrimps the oxygen affinity of hemocyanin from U. pusilla is increased upon addition of l-lactate. A particular feature of this hemocyanin seems to be that l-lactate already enhances oxygen affinity under resting conditions which possibly compensates the rather low intrinsic affinity observed in absence of l-lactate. The fast rate of oxygen dissociation might indicate that in this hemocyanin a higher cooperativity is less important than a fast response of saturation level to changes in oxygen concentration.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/3989615" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="6086c810d10d97401a24da337c000927" rel="nofollow" data-download="{"attachment_id":50095105,"asset_id":3989615,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/50095105/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="3511874" href="https://cnrs.academia.edu/MarcoPaoli">Marco Paoli</a><script data-card-contents-for-user="3511874" type="text/json">{"id":3511874,"first_name":"Marco","last_name":"Paoli","domain_name":"cnrs","page_name":"MarcoPaoli","display_name":"Marco Paoli","profile_url":"https://cnrs.academia.edu/MarcoPaoli?f_ri=1970697","photo":"https://0.academia-photos.com/3511874/1201254/32743257/s65_marco.paoli.jpg"}</script></span></span></li><li class="js-paper-rank-work_3989615 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="3989615"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 3989615, container: ".js-paper-rank-work_3989615", }); });</script></li><li class="js-percentile-work_3989615 InlineList-item InlineList-item--bordered hidden u-tcGrayDark"><span class="percentile-widget hidden"><span class="u-mr2x percentile-widget" style="display: none">•</span><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 3989615; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-percentile-work_3989615"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></li><li class="js-view-count-work_3989615 InlineList-item InlineList-item--bordered hidden"><div><span><span class="js-view-count view-count u-mr2x" data-work-id="3989615"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 3989615; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=3989615]").text(description); $(".js-view-count-work_3989615").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_3989615").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="3989615"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">9</a>  </div><span class="InlineList-item-text u-textTruncate u-pl9x"><a class="InlineList-item-text" data-has-card-for-ri="4987" rel="nofollow" href="https://www.academia.edu/Documents/in/Kinetics">Kinetics</a>, <script data-card-contents-for-ri="4987" type="text/json">{"id":4987,"name":"Kinetics","url":"https://www.academia.edu/Documents/in/Kinetics?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="7049" rel="nofollow" href="https://www.academia.edu/Documents/in/Crustacea">Crustacea</a>, <script data-card-contents-for-ri="7049" type="text/json">{"id":7049,"name":"Crustacea","url":"https://www.academia.edu/Documents/in/Crustacea?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="30602" rel="nofollow" href="https://www.academia.edu/Documents/in/Crustacea_Decapoda">Crustacea Decapoda</a>, <script data-card-contents-for-ri="30602" type="text/json">{"id":30602,"name":"Crustacea Decapoda","url":"https://www.academia.edu/Documents/in/Crustacea_Decapoda?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="380825" rel="nofollow" href="https://www.academia.edu/Documents/in/Oxygen">Oxygen</a><script data-card-contents-for-ri="380825" type="text/json">{"id":380825,"name":"Oxygen","url":"https://www.academia.edu/Documents/in/Oxygen?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=3989615]'), work: {"id":3989615,"title":"Unusual oxygen binding behavior of a 24-meric crustacean hemocyanin","created_at":"2013-07-09T17:12:44.685-07:00","url":"https://www.academia.edu/3989615/Unusual_oxygen_binding_behavior_of_a_24_meric_crustacean_hemocyanin?f_ri=1970697","dom_id":"work_3989615","summary":"Hemocyanins from Crustacea usually are found as 1 × 6 or 2 × 6-meric assemblies. An exception is the hemocyanin isolated from thalassinidean shrimps where the main component is a 24-meric structure. Our analysis of oxygen binding data of the thalassinidean shrimp Upogebia pusilla based on a three-state MWC-model revealed that despite the 24-meric structure the functional properties can be described very well based on the hexamer as allosteric unit. In contrast to the hemocyanins from other thalassinidean shrimps the oxygen affinity of hemocyanin from U. pusilla is increased upon addition of l-lactate. A particular feature of this hemocyanin seems to be that l-lactate already enhances oxygen affinity under resting conditions which possibly compensates the rather low intrinsic affinity observed in absence of l-lactate. The fast rate of oxygen dissociation might indicate that in this hemocyanin a higher cooperativity is less important than a fast response of saturation level to changes in oxygen concentration.","downloadable_attachments":[{"id":50095105,"asset_id":3989615,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":3511874,"first_name":"Marco","last_name":"Paoli","domain_name":"cnrs","page_name":"MarcoPaoli","display_name":"Marco Paoli","profile_url":"https://cnrs.academia.edu/MarcoPaoli?f_ri=1970697","photo":"https://0.academia-photos.com/3511874/1201254/32743257/s65_marco.paoli.jpg"}],"research_interests":[{"id":4987,"name":"Kinetics","url":"https://www.academia.edu/Documents/in/Kinetics?f_ri=1970697","nofollow":true},{"id":7049,"name":"Crustacea","url":"https://www.academia.edu/Documents/in/Crustacea?f_ri=1970697","nofollow":true},{"id":30602,"name":"Crustacea Decapoda","url":"https://www.academia.edu/Documents/in/Crustacea_Decapoda?f_ri=1970697","nofollow":true},{"id":380825,"name":"Oxygen","url":"https://www.academia.edu/Documents/in/Oxygen?f_ri=1970697","nofollow":true},{"id":1010725,"name":"Protein Binding","url":"https://www.academia.edu/Documents/in/Protein_Binding?f_ri=1970697"},{"id":1681026,"name":"Biochemistry and cell biology","url":"https://www.academia.edu/Documents/in/Biochemistry_and_cell_biology?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"},{"id":2045377,"name":"Functional Properties","url":"https://www.academia.edu/Documents/in/Functional_Properties?f_ri=1970697"},{"id":2295489,"name":"Hemocyanin","url":"https://www.academia.edu/Documents/in/Hemocyanin?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_12906090 coauthored" data-work_id="12906090" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/12906090/Protective_role_for_type_1_metabotropic_glutamate_receptors_against_spike_and_wave_discharges_in_the_WAG_Rij_rat_model_of_absence_epilepsy">Protective role for type-1 metabotropic glutamate receptors against spike and wave discharges in the WAG/Rij rat model of absence epilepsy</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">Eight-month old WAG/Rij rats, which developed spontaneous occurring absence seizures, showed a reduced function of mGlu1 metabotropic glutamate receptors in the thalamus, as assessed by in vivo measurements of DHPG-stimulated... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_12906090" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">Eight-month old WAG/Rij rats, which developed spontaneous occurring absence seizures, showed a reduced function of mGlu1 metabotropic glutamate receptors in the thalamus, as assessed by in vivo measurements of DHPG-stimulated polyphosphoinositide hydrolysis, in the presence of the mGlu5 antagonist MPEP as compared to age-matched non-epileptic control rats. These symptomatic 8-month old WAG/Rij rats also showed lower levels of thalamic mGlu1a receptors than age-matched controls and 2-month old (pre-symptomatic) WAG/Rij rats, as detected by immunoblotting. Immunohistochemical and in situ hybridization analysis indicated that the reduced expression of mGlu1 receptors found in symptomatic WAG/Rij rats was confined to an area of the thalamus that excluded the ventroposterolateral nucleus. No mGlu1 receptor mRNA was detected in the reticular thalamic nucleus. Pharmacological manipulation of mGlu1 receptors had a strong impact on absence seizures in WAG/Rij rats. Systemic treatment with the mGlu1 receptor enhancer SYN119, corresponding to compound RO0711401, reduced spontaneous spike and wave discharges spike-wave discharges (SWDs) in epileptic rats. Subcutaneous doses of 10 mg/kg of SYN119 only reduced the incidence of SWDs, whereas higher doses (30 mg/kg) also reduced the mean duration of SWDs. In contrast, treatment with the non-competitive mGlu1 receptor antagonist, JNJ16259685 (2.5 and 5 mg/kg, i.p.) increased the incidence of SWDs. These data suggest that absence epilepsy might be associated with a reduction of mGlu1 receptors in the thalamus, and that compounds that amplify the activity of mGlu1 receptors might be developed as novel anti-absence drugs.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/12906090" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="46f65a2614c46ef1e5aeb4b0150dab5c" rel="nofollow" data-download="{"attachment_id":45854732,"asset_id":12906090,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/45854732/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="33151002" href="https://independent.academia.edu/RNgomba">R. Ngomba</a><script data-card-contents-for-user="33151002" type="text/json">{"id":33151002,"first_name":"R.","last_name":"Ngomba","domain_name":"independent","page_name":"RNgomba","display_name":"R. Ngomba","profile_url":"https://independent.academia.edu/RNgomba?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span><span class="u-displayInlineBlock InlineList-item-text"> and <span class="u-textDecorationUnderline u-clickable InlineList-item-text js-work-more-authors-12906090">+3</span><div class="hidden js-additional-users-12906090"><div><span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a href="https://independent.academia.edu/ISantolini">I. Santolini</a></span></div><div><span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a href="https://wwwuniroma1.academia.edu/RobertoGradini">Roberto Gradini</a></span></div><div><span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a href="https://radboud.academia.edu/GillesvanLuijtelaar">Gilles van Luijtelaar</a></span></div></div></span><script>(function(){ var popoverSettings = { el: $('.js-work-more-authors-12906090'), placement: 'bottom', hide_delay: 200, html: true, content: function(){ return $('.js-additional-users-12906090').html(); } } new HoverPopover(popoverSettings); })();</script></li><li class="js-paper-rank-work_12906090 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="12906090"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 12906090, container: ".js-paper-rank-work_12906090", }); 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$(".js-view-count[data-work-id=12906090]").text(description); $(".js-view-count-work_12906090").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_12906090").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="12906090"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">15</a>  </div><span class="InlineList-item-text u-textTruncate u-pl10x"><a class="InlineList-item-text" data-has-card-for-ri="156" rel="nofollow" href="https://www.academia.edu/Documents/in/Genetics">Genetics</a>, <script data-card-contents-for-ri="156" type="text/json">{"id":156,"name":"Genetics","url":"https://www.academia.edu/Documents/in/Genetics?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="221" rel="nofollow" href="https://www.academia.edu/Documents/in/Psychology">Psychology</a>, <script data-card-contents-for-ri="221" type="text/json">{"id":221,"name":"Psychology","url":"https://www.academia.edu/Documents/in/Psychology?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="7955" rel="nofollow" href="https://www.academia.edu/Documents/in/Neuropharmacology">Neuropharmacology</a>, <script data-card-contents-for-ri="7955" type="text/json">{"id":7955,"name":"Neuropharmacology","url":"https://www.academia.edu/Documents/in/Neuropharmacology?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="10904" rel="nofollow" href="https://www.academia.edu/Documents/in/Electroencephalography">Electroencephalography</a><script data-card-contents-for-ri="10904" type="text/json">{"id":10904,"name":"Electroencephalography","url":"https://www.academia.edu/Documents/in/Electroencephalography?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=12906090]'), work: {"id":12906090,"title":"Protective role for type-1 metabotropic glutamate receptors against spike and wave discharges in the WAG/Rij rat model of absence epilepsy","created_at":"2015-06-10T09:23:18.328-07:00","url":"https://www.academia.edu/12906090/Protective_role_for_type_1_metabotropic_glutamate_receptors_against_spike_and_wave_discharges_in_the_WAG_Rij_rat_model_of_absence_epilepsy?f_ri=1970697","dom_id":"work_12906090","summary":"Eight-month old WAG/Rij rats, which developed spontaneous occurring absence seizures, showed a reduced function of mGlu1 metabotropic glutamate receptors in the thalamus, as assessed by in vivo measurements of DHPG-stimulated polyphosphoinositide hydrolysis, in the presence of the mGlu5 antagonist MPEP as compared to age-matched non-epileptic control rats. These symptomatic 8-month old WAG/Rij rats also showed lower levels of thalamic mGlu1a receptors than age-matched controls and 2-month old (pre-symptomatic) WAG/Rij rats, as detected by immunoblotting. Immunohistochemical and in situ hybridization analysis indicated that the reduced expression of mGlu1 receptors found in symptomatic WAG/Rij rats was confined to an area of the thalamus that excluded the ventroposterolateral nucleus. No mGlu1 receptor mRNA was detected in the reticular thalamic nucleus. Pharmacological manipulation of mGlu1 receptors had a strong impact on absence seizures in WAG/Rij rats. Systemic treatment with the mGlu1 receptor enhancer SYN119, corresponding to compound RO0711401, reduced spontaneous spike and wave discharges spike-wave discharges (SWDs) in epileptic rats. Subcutaneous doses of 10 mg/kg of SYN119 only reduced the incidence of SWDs, whereas higher doses (30 mg/kg) also reduced the mean duration of SWDs. In contrast, treatment with the non-competitive mGlu1 receptor antagonist, JNJ16259685 (2.5 and 5 mg/kg, i.p.) increased the incidence of SWDs. These data suggest that absence epilepsy might be associated with a reduction of mGlu1 receptors in the thalamus, and that compounds that amplify the activity of mGlu1 receptors might be developed as novel anti-absence drugs.","downloadable_attachments":[{"id":45854732,"asset_id":12906090,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":33151002,"first_name":"R.","last_name":"Ngomba","domain_name":"independent","page_name":"RNgomba","display_name":"R. Ngomba","profile_url":"https://independent.academia.edu/RNgomba?f_ri=1970697","photo":"/images/s65_no_pic.png"},{"id":33113199,"first_name":"I.","last_name":"Santolini","domain_name":"independent","page_name":"ISantolini","display_name":"I. Santolini","profile_url":"https://independent.academia.edu/ISantolini?f_ri=1970697","photo":"/images/s65_no_pic.png"},{"id":32067445,"first_name":"Roberto","last_name":"Gradini","domain_name":"wwwuniroma1","page_name":"RobertoGradini","display_name":"Roberto Gradini","profile_url":"https://wwwuniroma1.academia.edu/RobertoGradini?f_ri=1970697","photo":"https://0.academia-photos.com/32067445/9574779/10665808/s65_roberto.gradini.jpg"},{"id":31719244,"first_name":"Gilles","last_name":"van Luijtelaar","domain_name":"radboud","page_name":"GillesvanLuijtelaar","display_name":"Gilles van 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regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"},{"id":2246318,"name":"Motor activity","url":"https://www.academia.edu/Documents/in/Motor_activity?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_14860615 coauthored" data-work_id="14860615" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/14860615/Load_Induced_Modulation_of_Signal_Transduction_Networks">Load-Induced Modulation of Signal Transduction Networks</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest">This information is current as of 12 October 2011.</div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/14860615" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="53210db62bd793f325707650ac26b16c" rel="nofollow" data-download="{"attachment_id":43836275,"asset_id":14860615,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/43836275/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" 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js-work-more-authors-14860615">+2</span><div class="hidden js-additional-users-14860615"><div><span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a href="https://independent.academia.edu/AlexanderNinfa">Alexander Ninfa</a></span></div><div><span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a href="https://umich.academia.edu/PengJiang">Peng Jiang</a></span></div></div></span><script>(function(){ var popoverSettings = { el: $('.js-work-more-authors-14860615'), placement: 'bottom', hide_delay: 200, html: true, content: function(){ return $('.js-additional-users-14860615').html(); } } new HoverPopover(popoverSettings); })();</script></li><li class="js-paper-rank-work_14860615 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="14860615"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new 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2011.","downloadable_attachments":[{"id":43836275,"asset_id":14860615,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":33832547,"first_name":"eduardo","last_name":"sontag","domain_name":"rutgers","page_name":"eduardosontag","display_name":"eduardo sontag","profile_url":"https://rutgers.academia.edu/eduardosontag?f_ri=1970697","photo":"https://0.academia-photos.com/33832547/10316884/11512562/s65_eduardo.sontag.jpg"},{"id":34255505,"first_name":"Alexander","last_name":"Ninfa","domain_name":"independent","page_name":"AlexanderNinfa","display_name":"Alexander Ninfa","profile_url":"https://independent.academia.edu/AlexanderNinfa?f_ri=1970697","photo":"/images/s65_no_pic.png"},{"id":33909814,"first_name":"Peng","last_name":"Jiang","domain_name":"umich","page_name":"PengJiang","display_name":"Peng Jiang","profile_url":"https://umich.academia.edu/PengJiang?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":5400,"name":"Systems 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js-work-card work_7660172" data-work_id="7660172" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/7660172/Normal_Mode_Analysis_of_Biomolecular_Structures_Functional_Mechanisms_of_Membrane_Proteins">Normal Mode Analysis of Biomolecular Structures: Functional Mechanisms of Membrane Proteins</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">before joining the University of Pittsburgh. Her research areas are biomolecular systems structure, dynamics, and interactions. She authored in over 170 papers in the areas of polymer chemistry, molecular biophysics, and computational... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_7660172" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">before joining the University of Pittsburgh. Her research areas are biomolecular systems structure, dynamics, and interactions. She authored in over 170 papers in the areas of polymer chemistry, molecular biophysics, and computational structural biology. She has been an elected member of EMBO since</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/7660172" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="ac7d13b5008b24527ccb10f797878495" rel="nofollow" data-download="{"attachment_id":48380475,"asset_id":7660172,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/48380475/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="13895689" href="https://independent.academia.edu/AhmetBakan">Ahmet Bakan</a><script data-card-contents-for-user="13895689" type="text/json">{"id":13895689,"first_name":"Ahmet","last_name":"Bakan","domain_name":"independent","page_name":"AhmetBakan","display_name":"Ahmet Bakan","profile_url":"https://independent.academia.edu/AhmetBakan?f_ri=1970697","photo":"https://gravatar.com/avatar/5c0729cf20eba978734a824b979b7413?s=65"}</script></span></span></li><li class="js-paper-rank-work_7660172 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="7660172"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 7660172, container: ".js-paper-rank-work_7660172", }); 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Her research areas are biomolecular systems structure, dynamics, and interactions. She authored in over 170 papers in the areas of polymer chemistry, molecular biophysics, and computational structural biology. She has been an elected member of EMBO since","downloadable_attachments":[{"id":48380475,"asset_id":7660172,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":13895689,"first_name":"Ahmet","last_name":"Bakan","domain_name":"independent","page_name":"AhmetBakan","display_name":"Ahmet Bakan","profile_url":"https://independent.academia.edu/AhmetBakan?f_ri=1970697","photo":"https://gravatar.com/avatar/5c0729cf20eba978734a824b979b7413?s=65"}],"research_interests":[{"id":11298,"name":"Membrane Proteins","url":"https://www.academia.edu/Documents/in/Membrane_Proteins?f_ri=1970697","nofollow":true},{"id":260118,"name":"CHEMICAL SCIENCES","url":"https://www.academia.edu/Documents/in/CHEMICAL_SCIENCES?f_ri=1970697","nofollow":true},{"id":653665,"name":"Protein Conformation","url":"https://www.academia.edu/Documents/in/Protein_Conformation?f_ri=1970697","nofollow":true},{"id":900881,"name":"Membrane Protein","url":"https://www.academia.edu/Documents/in/Membrane_Protein?f_ri=1970697","nofollow":true},{"id":984606,"name":"Normal Mode Analysis","url":"https://www.academia.edu/Documents/in/Normal_Mode_Analysis?f_ri=1970697"},{"id":1011864,"name":"Structure Function","url":"https://www.academia.edu/Documents/in/Structure_Function?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_11949203" data-work_id="11949203" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/11949203/Inhibiting_the_HIV_integration_process_past_present_and_the_future">Inhibiting the HIV integration process: past, present, and the future</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">HIV integrase (IN) catalyzes the insertion into the genome of the infected human cell of viral DNA produced by the retrotranscription process. The discovery of raltegravir validated the existence of the IN, which is a new target in the... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_11949203" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">HIV integrase (IN) catalyzes the insertion into the genome of the infected human cell of viral DNA produced by the retrotranscription process. The discovery of raltegravir validated the existence of the IN, which is a new target in the field of anti-HIV drug research. The mechanism of catalysis of IN is depicted, and the characteristics of the inhibitors of the catalytic site of this viral enzyme are reported. The role played by the resistance is elucidated, as well as the possibility of bypassing this problem. New approaches to block the integration process are depicted as future perspectives, such as development of allosteric IN inhibitors, dual inhibitors targeting both IN and other enzymes, inhibitors of enzymes that activate IN, activators of IN activity, as well as a gene therapy approach.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/11949203" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="c42c22145ce594fcde9935bcf68447b8" rel="nofollow" data-download="{"attachment_id":46425603,"asset_id":11949203,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/46425603/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="29618205" href="https://independent.academia.edu/SantoRobertoDi">Roberto Di Santo</a><script data-card-contents-for-user="29618205" type="text/json">{"id":29618205,"first_name":"Roberto Di","last_name":"Santo","domain_name":"independent","page_name":"SantoRobertoDi","display_name":"Roberto Di Santo","profile_url":"https://independent.academia.edu/SantoRobertoDi?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_11949203 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="11949203"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 11949203, container: ".js-paper-rank-work_11949203", }); 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$(".js-view-count[data-work-id=11949203]").text(description); $(".js-view-count-work_11949203").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_11949203").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="11949203"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">7</a>  </div><span class="InlineList-item-text u-textTruncate u-pl9x"><a class="InlineList-item-text" data-has-card-for-ri="531" rel="nofollow" href="https://www.academia.edu/Documents/in/Organic_Chemistry">Organic Chemistry</a>, <script data-card-contents-for-ri="531" type="text/json">{"id":531,"name":"Organic Chemistry","url":"https://www.academia.edu/Documents/in/Organic_Chemistry?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="2375" rel="nofollow" href="https://www.academia.edu/Documents/in/Medicinal_Chemistry">Medicinal Chemistry</a>, <script data-card-contents-for-ri="2375" type="text/json">{"id":2375,"name":"Medicinal Chemistry","url":"https://www.academia.edu/Documents/in/Medicinal_Chemistry?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="39978" rel="nofollow" href="https://www.academia.edu/Documents/in/HIV">HIV</a>, <script data-card-contents-for-ri="39978" type="text/json">{"id":39978,"name":"HIV","url":"https://www.academia.edu/Documents/in/HIV?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="653665" rel="nofollow" href="https://www.academia.edu/Documents/in/Protein_Conformation">Protein Conformation</a><script data-card-contents-for-ri="653665" type="text/json">{"id":653665,"name":"Protein Conformation","url":"https://www.academia.edu/Documents/in/Protein_Conformation?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=11949203]'), work: {"id":11949203,"title":"Inhibiting the HIV integration process: past, present, and the future","created_at":"2015-04-14T15:13:28.792-07:00","url":"https://www.academia.edu/11949203/Inhibiting_the_HIV_integration_process_past_present_and_the_future?f_ri=1970697","dom_id":"work_11949203","summary":"HIV integrase (IN) catalyzes the insertion into the genome of the infected human cell of viral DNA produced by the retrotranscription process. The discovery of raltegravir validated the existence of the IN, which is a new target in the field of anti-HIV drug research. The mechanism of catalysis of IN is depicted, and the characteristics of the inhibitors of the catalytic site of this viral enzyme are reported. The role played by the resistance is elucidated, as well as the possibility of bypassing this problem. New approaches to block the integration process are depicted as future perspectives, such as development of allosteric IN inhibitors, dual inhibitors targeting both IN and other enzymes, inhibitors of enzymes that activate IN, activators of IN activity, as well as a gene therapy approach.","downloadable_attachments":[{"id":46425603,"asset_id":11949203,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":29618205,"first_name":"Roberto Di","last_name":"Santo","domain_name":"independent","page_name":"SantoRobertoDi","display_name":"Roberto Di Santo","profile_url":"https://independent.academia.edu/SantoRobertoDi?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":531,"name":"Organic Chemistry","url":"https://www.academia.edu/Documents/in/Organic_Chemistry?f_ri=1970697","nofollow":true},{"id":2375,"name":"Medicinal 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class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/25421921/Linked_Analysis_of_Large_Cooperative_Allosteric_Systems_The_Case_of_the_Giant_HBL_Hemoglobins">Linked Analysis of Large Cooperative, Allosteric Systems: The Case of the Giant HBL Hemoglobins</a></div></div><div class="u-pb4x u-mt3x"></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/25421921" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="4a79b4dbbd80d7fedd54bdbe47deaae7" rel="nofollow" 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type="text/json">{"id":4987,"name":"Kinetics","url":"https://www.academia.edu/Documents/in/Kinetics?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="94218" rel="nofollow" href="https://www.academia.edu/Documents/in/Link_analysis">Link analysis</a>, <script data-card-contents-for-ri="94218" type="text/json">{"id":94218,"name":"Link analysis","url":"https://www.academia.edu/Documents/in/Link_analysis?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="201412" rel="nofollow" href="https://www.academia.edu/Documents/in/Oligochaeta">Oligochaeta</a><script data-card-contents-for-ri="201412" type="text/json">{"id":201412,"name":"Oligochaeta","url":"https://www.academia.edu/Documents/in/Oligochaeta?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=25421921]'), work: {"id":25421921,"title":"Linked Analysis 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class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/18042708/Allosteric_Modulation_of_Dopamine_D_2_Receptors_by_Homocysteine">Allosteric Modulation of Dopamine D 2 Receptors by Homocysteine</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">It has been suggested that L-DOPA-induced hyperhomocysteinemia can increase the risk of stroke, heart disease, and dementia and is an additional pathogenetic factor involved in the progression of Parkinson's disease. In Chinese hamster... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_18042708" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">It has been suggested that L-DOPA-induced hyperhomocysteinemia can increase the risk of stroke, heart disease, and dementia and is an additional pathogenetic factor involved in the progression of Parkinson's disease. In Chinese hamster ovary (CHO) cells stably cotransfected with adenosine A 2A and dopamine D 2 receptors, homocysteine selectively decreased the ability of D 2 receptor stimulation to internalize adenosine A 2A -dopamine D 2 receptor complexes. Radioligand-binding experiments in the same cell line demonstrated that homocysteine acts as an allosteric D 2 receptor antagonist, by selectively reducing the affinity of D 2 receptors for agonists but not for antagonists. Mass spectrometric analysis showed that, by means of an arginine (Arg)-thiol electrostatic interaction, homocysteine forms noncovalent complexes with the two Arg-rich epitopes of the third intracellular loop of the D 2 receptor, one of them involved in A 2A -D 2 receptor heteromerization. However, homocysteine was unable to prevent or disrupt A 2A -D 2 receptor heteromerization, as demonstrated with Fluorescence Resonance Energy Transfer (FRET) experiments in stably cotransfected HEK cells. The present results could have implications for Parkinson's disease.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/18042708" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="b85a3af3739062c7a87a5949ee6e57e6" rel="nofollow" data-download="{"attachment_id":39844734,"asset_id":18042708,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/39844734/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="37980013" href="https://independent.academia.edu/PaulinaCarriba">Paulina Carriba</a><script data-card-contents-for-user="37980013" type="text/json">{"id":37980013,"first_name":"Paulina","last_name":"Carriba","domain_name":"independent","page_name":"PaulinaCarriba","display_name":"Paulina Carriba","profile_url":"https://independent.academia.edu/PaulinaCarriba?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span><span class="u-displayInlineBlock InlineList-item-text"> and <span class="u-textDecorationUnderline u-clickable InlineList-item-text js-work-more-authors-18042708">+2</span><div class="hidden js-additional-users-18042708"><div><span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a href="https://ki.academia.edu/KjellFuxe">Kjell Fuxe</a></span></div><div><span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a href="https://independent.academia.edu/AminaWoods">Amina Woods</a></span></div></div></span><script>(function(){ var popoverSettings = { el: $('.js-work-more-authors-18042708'), placement: 'bottom', hide_delay: 200, html: true, content: function(){ return $('.js-additional-users-18042708').html(); 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In Chinese hamster ovary (CHO) cells stably cotransfected with adenosine A 2A and dopamine D 2 receptors, homocysteine selectively decreased the ability of D 2 receptor stimulation to internalize adenosine A 2A -dopamine D 2 receptor complexes. Radioligand-binding experiments in the same cell line demonstrated that homocysteine acts as an allosteric D 2 receptor antagonist, by selectively reducing the affinity of D 2 receptors for agonists but not for antagonists. Mass spectrometric analysis showed that, by means of an arginine (Arg)-thiol electrostatic interaction, homocysteine forms noncovalent complexes with the two Arg-rich epitopes of the third intracellular loop of the D 2 receptor, one of them involved in A 2A -D 2 receptor heteromerization. However, homocysteine was unable to prevent or disrupt A 2A -D 2 receptor heteromerization, as demonstrated with Fluorescence Resonance Energy Transfer (FRET) experiments in stably cotransfected HEK cells. The present results could have implications for Parkinson's disease.","downloadable_attachments":[{"id":39844734,"asset_id":18042708,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":37980013,"first_name":"Paulina","last_name":"Carriba","domain_name":"independent","page_name":"PaulinaCarriba","display_name":"Paulina Carriba","profile_url":"https://independent.academia.edu/PaulinaCarriba?f_ri=1970697","photo":"/images/s65_no_pic.png"},{"id":31184633,"first_name":"Kjell","last_name":"Fuxe","domain_name":"ki","page_name":"KjellFuxe","display_name":"Kjell Fuxe","profile_url":"https://ki.academia.edu/KjellFuxe?f_ri=1970697","photo":"/images/s65_no_pic.png"},{"id":32931058,"first_name":"Amina","last_name":"Woods","domain_name":"independent","page_name":"AminaWoods","display_name":"Amina Woods","profile_url":"https://independent.academia.edu/AminaWoods?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":5769,"name":"Mass 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An evaluation of the structure-activity relationships... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_14742133" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">A high-throughput screening campaign identified 4-((E)-styryl)-pyrimidin-2-ylamine (11) as a positive allosteric modulator of the metabotropic glutamate (mGlu) receptor subtype 4. 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An evaluation of the structure-activity relationships (SAR) of 11 is described and the efficacy of this compound in a haloperidol-induced catalepsy rat model following oral administration is presented.","downloadable_attachments":[{"id":43926560,"asset_id":14742133,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":33704770,"first_name":"Mark","last_name":"Gemkow","domain_name":"independent","page_name":"MarkGemkow","display_name":"Mark Gemkow","profile_url":"https://independent.academia.edu/MarkGemkow?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":531,"name":"Organic Chemistry","url":"https://www.academia.edu/Documents/in/Organic_Chemistry?f_ri=1970697","nofollow":true},{"id":61233,"name":"Glutamate","url":"https://www.academia.edu/Documents/in/Glutamate?f_ri=1970697","nofollow":true},{"id":88745,"name":"High throughput screening","url":"https://www.academia.edu/Documents/in/High_throughput_screening?f_ri=1970697","nofollow":true},{"id":99270,"name":"Metabotropic Glutamate Receptors","url":"https://www.academia.edu/Documents/in/Metabotropic_Glutamate_Receptors?f_ri=1970697","nofollow":true},{"id":151951,"name":"Animal Model","url":"https://www.academia.edu/Documents/in/Animal_Model?f_ri=1970697"},{"id":235677,"name":"Behavioral Animal Models","url":"https://www.academia.edu/Documents/in/Behavioral_Animal_Models?f_ri=1970697"},{"id":375054,"name":"Rats","url":"https://www.academia.edu/Documents/in/Rats?f_ri=1970697"},{"id":728493,"name":"Bioorganic and medicinal Chemistry","url":"https://www.academia.edu/Documents/in/Bioorganic_and_medicinal_Chemistry?f_ri=1970697"},{"id":732354,"name":"Rat Model","url":"https://www.academia.edu/Documents/in/Rat_Model?f_ri=1970697"},{"id":967839,"name":"Structure activity Relationship","url":"https://www.academia.edu/Documents/in/Structure_activity_Relationship?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"},{"id":2246318,"name":"Motor activity","url":"https://www.academia.edu/Documents/in/Motor_activity?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_28065073" data-work_id="28065073" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/28065073/Lac_repressor_operator_complex">Lac repressor—operator complex</a></div></div><div class="u-pb4x u-mt3x"></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/28065073" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="1fabf3b132b51db983c1c8e6a86a6f9c" rel="nofollow" data-download="{"attachment_id":48378811,"asset_id":28065073,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/48378811/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="52607257" href="https://independent.academia.edu/PonzyLu">Ponzy Lu</a><script data-card-contents-for-user="52607257" type="text/json">{"id":52607257,"first_name":"Ponzy","last_name":"Lu","domain_name":"independent","page_name":"PonzyLu","display_name":"Ponzy Lu","profile_url":"https://independent.academia.edu/PonzyLu?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_28065073 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="28065073"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 28065073, container: ".js-paper-rank-work_28065073", }); 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They control development, fertility, gametogenesis and are misregulated in many cancers. Their enormous... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_11953012" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">Nuclear receptors (NRs) form a large superfamily of transcription factors that participate in virtually every key biological process. They control development, fertility, gametogenesis and are misregulated in many cancers. Their enormous functional plasticity as transcription factors relates in part to NR-mediated interactions with hundreds of coregulatory proteins upon ligand (e.g., hormone) binding to their ligand binding domains (LBD), or following covalent modification. Some coregulator association relates to the distinct residues that shape a coactivator binding pocket termed AF-2, a surface groove that primarily determines the preference and specificity of protein-protein interactions. However, the highly conserved AF-2 pocket in the NR superfamily appears to be insufficient to account for NR subtype specificity leading to fine transcriptional modulation in certain settings. Additional protein-protein interaction surfaces, most notably on their LBD, may contribute to modulating NR function. NR coregulators and chaperones, normally much larger than the NR itself, may also bind to such interfaces. In the case of the androgen receptor (AR) LBD surface, structural and functional data highlighted the presence of another site named BF-3, which lies at a distinct but topographically adjacent surface to AF-2. AR BF-3 is a hot spot for mutations involved in prostate cancer and androgen insensitivity syndromes, and some FDA-approved drugs bind at this site. Structural studies suggested an allosteric relationship between AF-2 and BF-3, as occupancy of the latter affected coactivator recruitment to AF-2. Physiological relevant partners of AR BF-3 have not been described as yet. The newly discovered site is highly conserved among the steroid receptors subclass, but is also present in other NRs. Several missense mutations in the BF-3 regions of these human NRs are implicated in pathology and affect their function in vitro. The fact that AR BF-3 pocket is a druggable site evidences its pharmacological potential. Compounds that may affect allosterically NR function by binding to BF-3 open promising avenues to develop type-specific NR modulators.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/11953012" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="75c519027235be8631bf251a23669a5f" rel="nofollow" data-download="{"attachment_id":37311141,"asset_id":11953012,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/37311141/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="29639502" href="https://ub.academia.edu/EvaEst%C3%A9banezPerpi%C3%B1%C3%A1">Eva Estébanez-Perpiñá</a><script data-card-contents-for-user="29639502" type="text/json">{"id":29639502,"first_name":"Eva","last_name":"Estébanez-Perpiñá","domain_name":"ub","page_name":"EvaEstébanezPerpiñá","display_name":"Eva Estébanez-Perpiñá","profile_url":"https://ub.academia.edu/EvaEst%C3%A9banezPerpi%C3%B1%C3%A1?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_11953012 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="11953012"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 11953012, container: ".js-paper-rank-work_11953012", }); 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$(".js-view-count[data-work-id=11953012]").text(description); $(".js-view-count-work_11953012").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_11953012").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="11953012"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">15</a>  </div><span class="InlineList-item-text u-textTruncate u-pl10x"><a class="InlineList-item-text" data-has-card-for-ri="12980" rel="nofollow" href="https://www.academia.edu/Documents/in/Prostate_Cancer">Prostate Cancer</a>, <script data-card-contents-for-ri="12980" type="text/json">{"id":12980,"name":"Prostate Cancer","url":"https://www.academia.edu/Documents/in/Prostate_Cancer?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="42130" rel="nofollow" href="https://www.academia.edu/Documents/in/Nuclear_Receptor">Nuclear Receptor</a>, <script data-card-contents-for-ri="42130" type="text/json">{"id":42130,"name":"Nuclear Receptor","url":"https://www.academia.edu/Documents/in/Nuclear_Receptor?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="47884" rel="nofollow" href="https://www.academia.edu/Documents/in/Biological_Sciences">Biological Sciences</a>, <script data-card-contents-for-ri="47884" type="text/json">{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="50487" rel="nofollow" href="https://www.academia.edu/Documents/in/Protein-Protein_Interaction">Protein-Protein Interaction</a><script data-card-contents-for-ri="50487" type="text/json">{"id":50487,"name":"Protein-Protein Interaction","url":"https://www.academia.edu/Documents/in/Protein-Protein_Interaction?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=11953012]'), work: {"id":11953012,"title":"A conserved surface on the ligand binding domain of nuclear receptors for allosteric control","created_at":"2015-04-15T00:02:03.371-07:00","url":"https://www.academia.edu/11953012/A_conserved_surface_on_the_ligand_binding_domain_of_nuclear_receptors_for_allosteric_control?f_ri=1970697","dom_id":"work_11953012","summary":"Nuclear receptors (NRs) form a large superfamily of transcription factors that participate in virtually every key biological process. They control development, fertility, gametogenesis and are misregulated in many cancers. Their enormous functional plasticity as transcription factors relates in part to NR-mediated interactions with hundreds of coregulatory proteins upon ligand (e.g., hormone) binding to their ligand binding domains (LBD), or following covalent modification. Some coregulator association relates to the distinct residues that shape a coactivator binding pocket termed AF-2, a surface groove that primarily determines the preference and specificity of protein-protein interactions. However, the highly conserved AF-2 pocket in the NR superfamily appears to be insufficient to account for NR subtype specificity leading to fine transcriptional modulation in certain settings. Additional protein-protein interaction surfaces, most notably on their LBD, may contribute to modulating NR function. NR coregulators and chaperones, normally much larger than the NR itself, may also bind to such interfaces. In the case of the androgen receptor (AR) LBD surface, structural and functional data highlighted the presence of another site named BF-3, which lies at a distinct but topographically adjacent surface to AF-2. AR BF-3 is a hot spot for mutations involved in prostate cancer and androgen insensitivity syndromes, and some FDA-approved drugs bind at this site. Structural studies suggested an allosteric relationship between AF-2 and BF-3, as occupancy of the latter affected coactivator recruitment to AF-2. Physiological relevant partners of AR BF-3 have not been described as yet. The newly discovered site is highly conserved among the steroid receptors subclass, but is also present in other NRs. Several missense mutations in the BF-3 regions of these human NRs are implicated in pathology and affect their function in vitro. The fact that AR BF-3 pocket is a druggable site evidences its pharmacological potential. Compounds that may affect allosterically NR function by binding to BF-3 open promising avenues to develop type-specific NR modulators.","downloadable_attachments":[{"id":37311141,"asset_id":11953012,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":29639502,"first_name":"Eva","last_name":"Estébanez-Perpiñá","domain_name":"ub","page_name":"EvaEstébanezPerpiñá","display_name":"Eva Estébanez-Perpiñá","profile_url":"https://ub.academia.edu/EvaEst%C3%A9banezPerpi%C3%B1%C3%A1?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":12980,"name":"Prostate Cancer","url":"https://www.academia.edu/Documents/in/Prostate_Cancer?f_ri=1970697","nofollow":true},{"id":42130,"name":"Nuclear Receptor","url":"https://www.academia.edu/Documents/in/Nuclear_Receptor?f_ri=1970697","nofollow":true},{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences?f_ri=1970697","nofollow":true},{"id":50487,"name":"Protein-Protein Interaction","url":"https://www.academia.edu/Documents/in/Protein-Protein_Interaction?f_ri=1970697","nofollow":true},{"id":50630,"name":"Crystal structure","url":"https://www.academia.edu/Documents/in/Crystal_structure?f_ri=1970697"},{"id":74780,"name":"Mutation","url":"https://www.academia.edu/Documents/in/Mutation?f_ri=1970697"},{"id":213901,"name":"Transcription Factor","url":"https://www.academia.edu/Documents/in/Transcription_Factor?f_ri=1970697"},{"id":319122,"name":"Surface Structure","url":"https://www.academia.edu/Documents/in/Surface_Structure?f_ri=1970697"},{"id":342071,"name":"Hot Spot","url":"https://www.academia.edu/Documents/in/Hot_Spot?f_ri=1970697"},{"id":440924,"name":"Surface Properties","url":"https://www.academia.edu/Documents/in/Surface_Properties?f_ri=1970697"},{"id":495625,"name":"Biological Process","url":"https://www.academia.edu/Documents/in/Biological_Process?f_ri=1970697"},{"id":590252,"name":"Androgen Receptor","url":"https://www.academia.edu/Documents/in/Androgen_Receptor?f_ri=1970697"},{"id":798198,"name":"Androgen Insensitivity Syndrome","url":"https://www.academia.edu/Documents/in/Androgen_Insensitivity_Syndrome?f_ri=1970697"},{"id":809881,"name":"Amino Acid Sequence","url":"https://www.academia.edu/Documents/in/Amino_Acid_Sequence?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_25157026 coauthored" data-work_id="25157026" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/25157026/8_Fluoroimidazo_1_2_a_pyridine_Synthesis_physicochemical_properties_and_evaluation_as_a_bioisosteric_replacement_for_imidazo_1_2_a_pyrimidine_in_an_allosteric_modulator_ligand_of_the_GABAA_receptor">8-Fluoroimidazo[1,2-a]pyridine: Synthesis, physicochemical properties and evaluation as a bioisosteric replacement for imidazo[1,2-a]pyrimidine in an allosteric modulator ligand of the GABAA receptor</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">8-Fluoroimidazo[1,2-a]pyridine has been established as a physicochemical mimic of imidazo[1,2-a]pyrimidine, using both in silico and traditional techniques. Furthermore, a novel synthesis of a 3,7-disubstituted-8-fluoroimidazopyridine 3... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_25157026" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">8-Fluoroimidazo[1,2-a]pyridine has been established as a physicochemical mimic of imidazo[1,2-a]pyrimidine, using both in silico and traditional techniques. Furthermore, a novel synthesis of a 3,7-disubstituted-8-fluoroimidazopyridine 3 has been developed and the utility of the physicochemical mimicry has been demonstrated in an in vitro system. Here, the 8-fluoroimidazopyridine ring contained in ligand 3 acts as a bioisosteric replacement for imidazopyrimidine in the GABA A receptor modulator 2.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/25157026" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="391148e53dcb126b665d9358ee8cca35" rel="nofollow" data-download="{"attachment_id":45475538,"asset_id":25157026,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/45475538/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="48448546" href="https://evotec.academia.edu/DavidHallett">David Hallett</a><script data-card-contents-for-user="48448546" type="text/json">{"id":48448546,"first_name":"David","last_name":"Hallett","domain_name":"evotec","page_name":"DavidHallett","display_name":"David Hallett","profile_url":"https://evotec.academia.edu/DavidHallett?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span><span class="u-displayInlineBlock InlineList-item-text"> and <span class="u-textDecorationUnderline u-clickable InlineList-item-text js-work-more-authors-25157026">+1</span><div class="hidden js-additional-users-25157026"><div><span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a href="https://independent.academia.edu/MerchantKevin">Kevin Merchant</a></span></div></div></span><script>(function(){ var popoverSettings = { el: $('.js-work-more-authors-25157026'), placement: 'bottom', hide_delay: 200, html: true, content: function(){ return $('.js-additional-users-25157026').html(); 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Furthermore, a novel synthesis of a 3,7-disubstituted-8-fluoroimidazopyridine 3 has been developed and the utility of the physicochemical mimicry has been demonstrated in an in vitro system. Here, the 8-fluoroimidazopyridine ring contained in ligand 3 acts as a bioisosteric replacement for imidazopyrimidine in the GABA A receptor modulator 2.","downloadable_attachments":[{"id":45475538,"asset_id":25157026,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":48448546,"first_name":"David","last_name":"Hallett","domain_name":"evotec","page_name":"DavidHallett","display_name":"David Hallett","profile_url":"https://evotec.academia.edu/DavidHallett?f_ri=1970697","photo":"/images/s65_no_pic.png"},{"id":48474677,"first_name":"Kevin","last_name":"Merchant","domain_name":"independent","page_name":"MerchantKevin","display_name":"Kevin Merchant","profile_url":"https://independent.academia.edu/MerchantKevin?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":531,"name":"Organic Chemistry","url":"https://www.academia.edu/Documents/in/Organic_Chemistry?f_ri=1970697","nofollow":true},{"id":84760,"name":"Mice","url":"https://www.academia.edu/Documents/in/Mice?f_ri=1970697","nofollow":true},{"id":490260,"name":"Pyridines","url":"https://www.academia.edu/Documents/in/Pyridines?f_ri=1970697","nofollow":true},{"id":498676,"name":"Lipophilicity","url":"https://www.academia.edu/Documents/in/Lipophilicity?f_ri=1970697","nofollow":true},{"id":728493,"name":"Bioorganic and medicinal Chemistry","url":"https://www.academia.edu/Documents/in/Bioorganic_and_medicinal_Chemistry?f_ri=1970697"},{"id":801409,"name":"Imidazoles","url":"https://www.academia.edu/Documents/in/Imidazoles?f_ri=1970697"},{"id":954995,"name":"Human Fibroblasts","url":"https://www.academia.edu/Documents/in/Human_Fibroblasts?f_ri=1970697"},{"id":967839,"name":"Structure activity Relationship","url":"https://www.academia.edu/Documents/in/Structure_activity_Relationship?f_ri=1970697"},{"id":990417,"name":"Recombinant Proteins","url":"https://www.academia.edu/Documents/in/Recombinant_Proteins?f_ri=1970697"},{"id":1222191,"name":"Ligands","url":"https://www.academia.edu/Documents/in/Ligands?f_ri=1970697"},{"id":1724844,"name":"Molecular Structure","url":"https://www.academia.edu/Documents/in/Molecular_Structure?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_14065685 coauthored" data-work_id="14065685" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/14065685/International_Union_of_Basic_and_Clinical_Pharmacology_XCIV_Adhesion_G_Protein_Coupled_Receptors">International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein-Coupled Receptors</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">The Adhesion family forms a large branch of the pharmacologically important superfamily of G protein-coupled receptors (GPCRs). As Adhesion GPCRs increasingly receive attention from a wide spectrum of biomedical fields, the Adhesion GPCR... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_14065685" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">The Adhesion family forms a large branch of the pharmacologically important superfamily of G protein-coupled receptors (GPCRs). As Adhesion GPCRs increasingly receive attention from a wide spectrum of biomedical fields, the Adhesion GPCR Consortium, together with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification, proposes a unified nomenclature for Adhesion GPCRs. The new names have ADGR as common dominator followed by a letter and a number to denote each subfamily and subtype, respectively. The new names, with old and alternative names within parentheses, are: ADGRA1 (GPR123), ADGRA2 (GPR124), ADGRA3 (GPR125), ADGRB1 (BAI1), ADGRB2 (BAI2), ADGRB3 (BAI3), ADGRC1 (CELSR1), ADGRC2 (CELSR2), ADGRC3 (CELSR3), ADGRD1 (GPR133), ADGRD2 (GPR144), ADGRE1 (EMR1, F4/80), ADGRE2 (EMR2), ADGRE3 (EMR3), ADGRE4 (EMR4), ADGRE5 (CD97), ADGRF1 (GPR110), ADGRF2 (GPR111), ADGRF3 (GPR113), ADGRF4 (GPR115), ADGRF5 (GPR116, Ig-Hepta), ADG...</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/14065685" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="664180b4bb82cc77262dffc8e920ac58" rel="nofollow" data-download="{"attachment_id":44643607,"asset_id":14065685,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/44643607/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="33081950" href="https://independent.academia.edu/MartinStacey2">Martin Stacey</a><script data-card-contents-for-user="33081950" type="text/json">{"id":33081950,"first_name":"Martin","last_name":"Stacey","domain_name":"independent","page_name":"MartinStacey2","display_name":"Martin Stacey","profile_url":"https://independent.academia.edu/MartinStacey2?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span><span class="u-displayInlineBlock InlineList-item-text"> and <span class="u-textDecorationUnderline u-clickable InlineList-item-text js-work-more-authors-14065685">+4</span><div class="hidden js-additional-users-14065685"><div><span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a href="https://uni-erlangen.academia.edu/FelixEngel">Felix Engel</a></span></div><div><span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a href="https://independent.academia.edu/GabrielaAust">Gabriela Aust</a></span></div><div><span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a href="https://independent.academia.edu/XianhuaPiao">Xianhua Piao</a></span></div><div><span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a href="https://independent.academia.edu/RobertFredriksson">Robert Fredriksson</a></span></div></div></span><script>(function(){ var popoverSettings = { el: $('.js-work-more-authors-14065685'), placement: 'bottom', hide_delay: 200, html: true, content: function(){ return $('.js-additional-users-14065685').html(); 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XCIV. Adhesion G Protein-Coupled Receptors","created_at":"2015-07-15T01:36:03.494-07:00","url":"https://www.academia.edu/14065685/International_Union_of_Basic_and_Clinical_Pharmacology_XCIV_Adhesion_G_Protein_Coupled_Receptors?f_ri=1970697","dom_id":"work_14065685","summary":"The Adhesion family forms a large branch of the pharmacologically important superfamily of G protein-coupled receptors (GPCRs). As Adhesion GPCRs increasingly receive attention from a wide spectrum of biomedical fields, the Adhesion GPCR Consortium, together with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification, proposes a unified nomenclature for Adhesion GPCRs. The new names have ADGR as common dominator followed by a letter and a number to denote each subfamily and subtype, respectively. The new names, with old and alternative names within parentheses, are: ADGRA1 (GPR123), ADGRA2 (GPR124), ADGRA3 (GPR125), ADGRB1 (BAI1), ADGRB2 (BAI2), ADGRB3 (BAI3), ADGRC1 (CELSR1), ADGRC2 (CELSR2), ADGRC3 (CELSR3), ADGRD1 (GPR133), ADGRD2 (GPR144), ADGRE1 (EMR1, F4/80), ADGRE2 (EMR2), ADGRE3 (EMR3), ADGRE4 (EMR4), ADGRE5 (CD97), ADGRF1 (GPR110), ADGRF2 (GPR111), ADGRF3 (GPR113), ADGRF4 (GPR115), ADGRF5 (GPR116, Ig-Hepta), ADG...","downloadable_attachments":[{"id":44643607,"asset_id":14065685,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":33081950,"first_name":"Martin","last_name":"Stacey","domain_name":"independent","page_name":"MartinStacey2","display_name":"Martin Stacey","profile_url":"https://independent.academia.edu/MartinStacey2?f_ri=1970697","photo":"/images/s65_no_pic.png"},{"id":35691534,"first_name":"Felix","last_name":"Engel","domain_name":"uni-erlangen","page_name":"FelixEngel","display_name":"Felix Engel","profile_url":"https://uni-erlangen.academia.edu/FelixEngel?f_ri=1970697","photo":"/images/s65_no_pic.png"},{"id":52109380,"first_name":"Gabriela","last_name":"Aust","domain_name":"independent","page_name":"GabrielaAust","display_name":"Gabriela Aust","profile_url":"https://independent.academia.edu/GabrielaAust?f_ri=1970697","photo":"/images/s65_no_pic.png"},{"id":33205791,"first_name":"Xianhua","last_name":"Piao","domain_name":"independent","page_name":"XianhuaPiao","display_name":"Xianhua Piao","profile_url":"https://independent.academia.edu/XianhuaPiao?f_ri=1970697","photo":"/images/s65_no_pic.png"},{"id":55001128,"first_name":"Robert","last_name":"Fredriksson","domain_name":"independent","page_name":"RobertFredriksson","display_name":"Robert Fredriksson","profile_url":"https://independent.academia.edu/RobertFredriksson?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":12571,"name":"Clinical Pharmacology","url":"https://www.academia.edu/Documents/in/Clinical_Pharmacology?f_ri=1970697","nofollow":true},{"id":31084,"name":"Ion Channels","url":"https://www.academia.edu/Documents/in/Ion_Channels?f_ri=1970697","nofollow":true},{"id":38831,"name":"Signal Transduction","url":"https://www.academia.edu/Documents/in/Signal_Transduction?f_ri=1970697","nofollow":true},{"id":41788,"name":"Cannabinoids","url":"https://www.academia.edu/Documents/in/Cannabinoids?f_ri=1970697","nofollow":true},{"id":54433,"name":"Phylogeny","url":"https://www.academia.edu/Documents/in/Phylogeny?f_ri=1970697"},{"id":86313,"name":"G protein-coupled receptors","url":"https://www.academia.edu/Documents/in/G_protein-coupled_receptors?f_ri=1970697"},{"id":375054,"name":"Rats","url":"https://www.academia.edu/Documents/in/Rats?f_ri=1970697"},{"id":386342,"name":"Sodium","url":"https://www.academia.edu/Documents/in/Sodium?f_ri=1970697"},{"id":466424,"name":"Internationality","url":"https://www.academia.edu/Documents/in/Internationality?f_ri=1970697"},{"id":653665,"name":"Protein Conformation","url":"https://www.academia.edu/Documents/in/Protein_Conformation?f_ri=1970697"},{"id":809881,"name":"Amino Acid Sequence","url":"https://www.academia.edu/Documents/in/Amino_Acid_Sequence?f_ri=1970697"},{"id":967839,"name":"Structure activity Relationship","url":"https://www.academia.edu/Documents/in/Structure_activity_Relationship?f_ri=1970697"},{"id":1137254,"name":"Hydrogen-Ion Concentration","url":"https://www.academia.edu/Documents/in/Hydrogen-Ion_Concentration?f_ri=1970697"},{"id":1212105,"name":"Molecular Targeted Therapy","url":"https://www.academia.edu/Documents/in/Molecular_Targeted_Therapy?f_ri=1970697"},{"id":1222191,"name":"Ligands","url":"https://www.academia.edu/Documents/in/Ligands?f_ri=1970697"},{"id":1809037,"name":"Dimerization","url":"https://www.academia.edu/Documents/in/Dimerization?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_14201524 coauthored" data-work_id="14201524" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/14201524/Progress_in_Structure_Based_Drug_Design_for_G_Protein_Coupled_Receptors">Progress in Structure Based Drug Design for G Protein-Coupled Receptors</a></div></div><div class="u-pb4x u-mt3x"></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/14201524" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="8a36f4af7ca45df340d9478c1363233e" rel="nofollow" data-download="{"attachment_id":44474585,"asset_id":14201524,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" 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class="u-displayInlineBlock InlineList-item-text"> and <span class="u-textDecorationUnderline u-clickable InlineList-item-text js-work-more-authors-14201524">+1</span><div class="hidden js-additional-users-14201524"><div><span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a href="https://independent.academia.edu/MilesCongreve">Miles Congreve</a></span></div></div></span><script>(function(){ var popoverSettings = { el: $('.js-work-more-authors-14201524'), placement: 'bottom', hide_delay: 200, html: true, content: function(){ return $('.js-additional-users-14201524').html(); } } new HoverPopover(popoverSettings); })();</script></li><li class="js-paper-rank-work_14201524 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="14201524"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 14201524, 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window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=14201524]").text(description); $(".js-view-count-work_14201524").attr('title', description).tooltip(); }); });</script></span><script>$(function() { $(".js-view-count-work_14201524").removeClass('hidden') })</script></div></li><li class="InlineList-item u-positionRelative" style="max-width: 250px"><div class="u-positionAbsolute" data-has-card-for-ri-list="14201524"><i class="fa fa-tag InlineList-item-icon u-positionRelative"></i>  <a class="InlineList-item-text u-positionRelative">8</a>  </div><span class="InlineList-item-text u-textTruncate u-pl9x"><a class="InlineList-item-text" data-has-card-for-ri="531" rel="nofollow" href="https://www.academia.edu/Documents/in/Organic_Chemistry">Organic Chemistry</a>, <script data-card-contents-for-ri="531" type="text/json">{"id":531,"name":"Organic Chemistry","url":"https://www.academia.edu/Documents/in/Organic_Chemistry?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="2375" rel="nofollow" href="https://www.academia.edu/Documents/in/Medicinal_Chemistry">Medicinal Chemistry</a>, <script data-card-contents-for-ri="2375" type="text/json">{"id":2375,"name":"Medicinal Chemistry","url":"https://www.academia.edu/Documents/in/Medicinal_Chemistry?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="86313" rel="nofollow" href="https://www.academia.edu/Documents/in/G_protein-coupled_receptors">G protein-coupled receptors</a>, <script data-card-contents-for-ri="86313" type="text/json">{"id":86313,"name":"G protein-coupled receptors","url":"https://www.academia.edu/Documents/in/G_protein-coupled_receptors?f_ri=1970697","nofollow":true}</script><a class="InlineList-item-text" data-has-card-for-ri="120789" rel="nofollow" href="https://www.academia.edu/Documents/in/Drug_Design">Drug Design</a><script data-card-contents-for-ri="120789" type="text/json">{"id":120789,"name":"Drug Design","url":"https://www.academia.edu/Documents/in/Drug_Design?f_ri=1970697","nofollow":true}</script></span></li><script>(function(){ if (true) { new Aedu.ResearchInterestListCard({ el: $('*[data-has-card-for-ri-list=14201524]'), work: {"id":14201524,"title":"Progress in Structure Based Drug Design for G Protein-Coupled Receptors","created_at":"2015-07-20T01:04:24.227-07:00","url":"https://www.academia.edu/14201524/Progress_in_Structure_Based_Drug_Design_for_G_Protein_Coupled_Receptors?f_ri=1970697","dom_id":"work_14201524","summary":null,"downloadable_attachments":[{"id":44474585,"asset_id":14201524,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":33188324,"first_name":"Fiona","last_name":"Marshall","domain_name":"independent","page_name":"FionaMarshall3","display_name":"Fiona Marshall","profile_url":"https://independent.academia.edu/FionaMarshall3?f_ri=1970697","photo":"/images/s65_no_pic.png"},{"id":33290309,"first_name":"Miles","last_name":"Congreve","domain_name":"independent","page_name":"MilesCongreve","display_name":"Miles Congreve","profile_url":"https://independent.academia.edu/MilesCongreve?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":531,"name":"Organic Chemistry","url":"https://www.academia.edu/Documents/in/Organic_Chemistry?f_ri=1970697","nofollow":true},{"id":2375,"name":"Medicinal Chemistry","url":"https://www.academia.edu/Documents/in/Medicinal_Chemistry?f_ri=1970697","nofollow":true},{"id":86313,"name":"G protein-coupled receptors","url":"https://www.academia.edu/Documents/in/G_protein-coupled_receptors?f_ri=1970697","nofollow":true},{"id":120789,"name":"Drug Design","url":"https://www.academia.edu/Documents/in/Drug_Design?f_ri=1970697","nofollow":true},{"id":446162,"name":"Medicinal","url":"https://www.academia.edu/Documents/in/Medicinal?f_ri=1970697"},{"id":653665,"name":"Protein Conformation","url":"https://www.academia.edu/Documents/in/Protein_Conformation?f_ri=1970697"},{"id":1222191,"name":"Ligands","url":"https://www.academia.edu/Documents/in/Ligands?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_23789060" data-work_id="23789060" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/23789060/Novel_2_and_4_Substituted_1_H_Imidazo_4_5_c_quinolin_4_amine_Derivatives_as_Allosteric_Modulators_of_the_A_3_Adenosine_Receptor">Novel 2- and 4-Substituted 1 H -Imidazo[4,5- c ]quinolin-4-amine Derivatives as Allosteric Modulators of the A 3 Adenosine Receptor</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">4-Arylamino and 2-cycloalkyl (including amino substitution) modifications were made in a series of 1H-imidazo-[4,5-c]quinolin-4-amine derivatives as allosteric modulators of the human A 3 adenosine receptor (AR). In addition to allosteric... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_23789060" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">4-Arylamino and 2-cycloalkyl (including amino substitution) modifications were made in a series of 1H-imidazo-[4,5-c]quinolin-4-amine derivatives as allosteric modulators of the human A 3 adenosine receptor (AR). In addition to allosteric modulation of the maximum functional efficacy (in [ 35 S]GTPγS G protein binding assay) of the A 3 AR agonist Cl-IB-MECA (15), some analogues also weakly inhibited equilibrium radioligand binding at ARs. 4-(3,5-Dichlorophenylamino) (6) or 2-(1-adamantyl) (20) substitution produced allosteric enhancement (twice the maximal agonist efficacy), with minimal inhibition of orthosteric AR binding. 2-(4-Tetrahydropyranyl) substitution abolished allosteric enhancement but preserved inhibition of orthosteric binding. Introduction of nitrogen in the six-membered ring at 2 position, to improve aqueous solubility and provide a derivatization site, greatly reduced the allosteric enhancement. 2-(4-(Benzoylamino)cyclohexyl) analogues 23 and 24 were weak negative A 3 AR modulators. Thus, consistent with previous findings, the allosteric and orthosteric inhibitory A 3 AR effects in imidazoquinolines are structurally separable, suggesting the possible design of additional derivatives with enhanced positive or negative allosteric A 3 AR activity and improved selectivity in comparison to inhibition of orthosteric binding.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/23789060" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="3695171b904d5105285dd2803769db91" rel="nofollow" data-download="{"attachment_id":44219112,"asset_id":23789060,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/44219112/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="46032474" href="https://independent.academia.edu/CastroSoniade">Sonia de Castro</a><script data-card-contents-for-user="46032474" type="text/json">{"id":46032474,"first_name":"Sonia de","last_name":"Castro","domain_name":"independent","page_name":"CastroSoniade","display_name":"Sonia de Castro","profile_url":"https://independent.academia.edu/CastroSoniade?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_23789060 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="23789060"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 23789060, container: ".js-paper-rank-work_23789060", }); 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In addition to allosteric modulation of the maximum functional efficacy (in [ 35 S]GTPγS G protein binding assay) of the A 3 AR agonist Cl-IB-MECA (15), some analogues also weakly inhibited equilibrium radioligand binding at ARs. 4-(3,5-Dichlorophenylamino) (6) or 2-(1-adamantyl) (20) substitution produced allosteric enhancement (twice the maximal agonist efficacy), with minimal inhibition of orthosteric AR binding. 2-(4-Tetrahydropyranyl) substitution abolished allosteric enhancement but preserved inhibition of orthosteric binding. Introduction of nitrogen in the six-membered ring at 2 position, to improve aqueous solubility and provide a derivatization site, greatly reduced the allosteric enhancement. 2-(4-(Benzoylamino)cyclohexyl) analogues 23 and 24 were weak negative A 3 AR modulators. Thus, consistent with previous findings, the allosteric and orthosteric inhibitory A 3 AR effects in imidazoquinolines are structurally separable, suggesting the possible design of additional derivatives with enhanced positive or negative allosteric A 3 AR activity and improved selectivity in comparison to inhibition of orthosteric binding.","downloadable_attachments":[{"id":44219112,"asset_id":23789060,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":46032474,"first_name":"Sonia de","last_name":"Castro","domain_name":"independent","page_name":"CastroSoniade","display_name":"Sonia de Castro","profile_url":"https://independent.academia.edu/CastroSoniade?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":531,"name":"Organic Chemistry","url":"https://www.academia.edu/Documents/in/Organic_Chemistry?f_ri=1970697","nofollow":true},{"id":2375,"name":"Medicinal Chemistry","url":"https://www.academia.edu/Documents/in/Medicinal_Chemistry?f_ri=1970697","nofollow":true},{"id":57808,"name":"Cell line","url":"https://www.academia.edu/Documents/in/Cell_line?f_ri=1970697","nofollow":true},{"id":432361,"name":"Radioligand Assay","url":"https://www.academia.edu/Documents/in/Radioligand_Assay?f_ri=1970697","nofollow":true},{"id":446162,"name":"Medicinal","url":"https://www.academia.edu/Documents/in/Medicinal?f_ri=1970697"},{"id":801409,"name":"Imidazoles","url":"https://www.academia.edu/Documents/in/Imidazoles?f_ri=1970697"},{"id":816974,"name":"Quinolines","url":"https://www.academia.edu/Documents/in/Quinolines?f_ri=1970697"},{"id":967839,"name":"Structure activity Relationship","url":"https://www.academia.edu/Documents/in/Structure_activity_Relationship?f_ri=1970697"},{"id":1222191,"name":"Ligands","url":"https://www.academia.edu/Documents/in/Ligands?f_ri=1970697"},{"id":1970697,"name":"Allosteric regulation","url":"https://www.academia.edu/Documents/in/Allosteric_regulation?f_ri=1970697"}]}, }) } })();</script></ul></li></ul></div></div><div class="u-borderBottom1 u-borderColorGrayLighter"><div class="clearfix u-pv7x u-mb0x js-work-card work_18576711" data-work_id="18576711" itemscope="itemscope" itemtype="https://schema.org/ScholarlyArticle"><div class="header"><div class="title u-fontSerif u-fs22 u-lineHeight1_3"><a class="u-tcGrayDarkest js-work-link" href="https://www.academia.edu/18576711/Thermal_unfolding_of_an_intermediate_is_associated_with_non_arrhenius_kinetics_in_the_folding_of_hen_lysozyme">Thermal unfolding of an intermediate is associated with non-arrhenius kinetics in the folding of hen lysozyme</a></div></div><div class="u-pb4x u-mt3x"><div class="summary u-fs14 u-fw300 u-lineHeight1_5 u-tcGrayDarkest"><div class="summarized">A variety of techniques, including quenched-flow hydrogen exchange labelling monitored by electrospray ionization mass spectrometry, and stopped-flow absorbance, fluorescence and circular dichroism spectroscopy, has been used to... <a class="more_link u-tcGrayDark u-linkUnstyled" data-container=".work_18576711" data-show=".complete" data-hide=".summarized" data-more-link-behavior="true" href="#">more</a></div><div class="complete hidden">A variety of techniques, including quenched-flow hydrogen exchange labelling monitored by electrospray ionization mass spectrometry, and stopped-flow absorbance, fluorescence and circular dichroism spectroscopy, has been used to investigate the refolding kinetics of hen lysozyme over a temperature range from 2 degrees C to 50 degrees C. Simple Arrhenius behaviour is not observed, and although the overall rate of folding increases from 2 to 40 degrees C, it decreases above 40 degrees C. In addition, the transient intermediate on the major folding pathway at 20 degrees C, in which the alpha-domain is persistently structured in the absence of a stable beta-domain, is thermally unfolded in a sigmoidal transition (T(m) approximately 40 degrees C) indicative of a cooperatively folded state. At all temperatures, however, there is evidence for fast ( approximately 25 %) and slow ( approximately 75 %) populations of refolding molecules. By using transition state theory, the kinetic data from various experiments were jointly fitted to a sequential three-state model for the slow folding pathway. Together with previous findings, these results indicate that the alpha-domain intermediate is a productive species on the folding route between the denatured and native states, and which accumulates as a consequence of its intrinsic stability. Our analysis suggests that the temperature dependence of the rate constant for lysozyme folding depends on both the total change in the heat capacity between the ground and transition states (the dominant factor at low temperatures) and the heat-induced destabilization of the alpha-domain intermediate (the dominant factor at high temperatures). Destabilization of such kinetically competent intermediate species is likely to be a determining factor in the non-Arrhenius temperature dependence of the folding rate of those proteins for which one or more intermediates are populated.</div></div></div><ul class="InlineList u-ph0x u-fs13"><li class="InlineList-item logged_in_only"><div class="share_on_academia_work_button"><a class="academia_share Button Button--inverseBlue Button--sm js-bookmark-button" data-academia-share="Work/18576711" data-share-source="work_strip" data-spinner="small_white_hide_contents"><i class="fa fa-plus"></i><span class="work-strip-link-text u-ml1x" data-content="button_text">Bookmark</span></a></div></li><li class="InlineList-item"><div class="download"><a id="c51f62c88bc3e1e967389ed11fbdb1d3" rel="nofollow" data-download="{"attachment_id":42158218,"asset_id":18576711,"asset_type":"Work","always_allow_download":false,"track":null,"button_location":"work_strip","source":null,"hide_modal":null}" class="Button Button--sm Button--inverseGreen js-download-button prompt_button doc_download" href="https://www.academia.edu/attachments/42158218/download_file?st=MTc0MDE1NDMyOSw4LjIyMi4yMDguMTQ2&s=work_strip"><i class="fa fa-arrow-circle-o-down fa-lg"></i><span class="u-textUppercase u-ml1x" data-content="button_text">Download</span></a></div></li><li class="InlineList-item"><ul class="InlineList InlineList--bordered u-ph0x"><li class="InlineList-item InlineList-item--bordered"><span class="InlineList-item-text">by <span itemscope="itemscope" itemprop="author" itemtype="https://schema.org/Person"><a class="u-tcGrayDark u-fw700" data-has-card-for-user="38613843" href="https://independent.academia.edu/MarcJamin">Marc Jamin</a><script data-card-contents-for-user="38613843" type="text/json">{"id":38613843,"first_name":"Marc","last_name":"Jamin","domain_name":"independent","page_name":"MarcJamin","display_name":"Marc Jamin","profile_url":"https://independent.academia.edu/MarcJamin?f_ri=1970697","photo":"/images/s65_no_pic.png"}</script></span></span></li><li class="js-paper-rank-work_18576711 InlineList-item InlineList-item--bordered hidden"><span class="js-paper-rank-view hidden u-tcGrayDark" data-paper-rank-work-id="18576711"><i class="u-m1x fa fa-bar-chart"></i><strong class="js-paper-rank"></strong></span><script>$(function() { new Works.PaperRankView({ workId: 18576711, container: ".js-paper-rank-work_18576711", }); 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Simple Arrhenius behaviour is not observed, and although the overall rate of folding increases from 2 to 40 degrees C, it decreases above 40 degrees C. In addition, the transient intermediate on the major folding pathway at 20 degrees C, in which the alpha-domain is persistently structured in the absence of a stable beta-domain, is thermally unfolded in a sigmoidal transition (T(m) approximately 40 degrees C) indicative of a cooperatively folded state. At all temperatures, however, there is evidence for fast ( approximately 25 %) and slow ( approximately 75 %) populations of refolding molecules. By using transition state theory, the kinetic data from various experiments were jointly fitted to a sequential three-state model for the slow folding pathway. Together with previous findings, these results indicate that the alpha-domain intermediate is a productive species on the folding route between the denatured and native states, and which accumulates as a consequence of its intrinsic stability. Our analysis suggests that the temperature dependence of the rate constant for lysozyme folding depends on both the total change in the heat capacity between the ground and transition states (the dominant factor at low temperatures) and the heat-induced destabilization of the alpha-domain intermediate (the dominant factor at high temperatures). Destabilization of such kinetically competent intermediate species is likely to be a determining factor in the non-Arrhenius temperature dependence of the folding rate of those proteins for which one or more intermediates are populated.","downloadable_attachments":[{"id":42158218,"asset_id":18576711,"asset_type":"Work","always_allow_download":false}],"ordered_authors":[{"id":38613843,"first_name":"Marc","last_name":"Jamin","domain_name":"independent","page_name":"MarcJamin","display_name":"Marc Jamin","profile_url":"https://independent.academia.edu/MarcJamin?f_ri=1970697","photo":"/images/s65_no_pic.png"}],"research_interests":[{"id":522,"name":"Thermodynamics","url":"https://www.academia.edu/Documents/in/Thermodynamics?f_ri=1970697","nofollow":true},{"id":2513,"name":"Molecular Biology","url":"https://www.academia.edu/Documents/in/Molecular_Biology?f_ri=1970697","nofollow":true},{"id":3771,"name":"Hydrogen","url":"https://www.academia.edu/Documents/in/Hydrogen?f_ri=1970697","nofollow":true},{"id":3971,"name":"Protein Folding","url":"https://www.academia.edu/Documents/in/Protein_Folding?f_ri=1970697","nofollow":true},{"id":4987,"name":"Kinetics","url":"https://www.academia.edu/Documents/in/Kinetics?f_ri=1970697"},{"id":5769,"name":"Mass Spectrometry","url":"https://www.academia.edu/Documents/in/Mass_Spectrometry?f_ri=1970697"},{"id":7698,"name":"Fluorescence","url":"https://www.academia.edu/Documents/in/Fluorescence?f_ri=1970697"},{"id":76407,"name":"Circular 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