PDB-101: Molecule of the Month: Ras Protein

<!DOCTYPE html> <html> <head> <script src="https://www.googletagmanager.com/gtag/js?id=G-EPQ9202NVY" async></script> <script> window.dataLayer = window.dataLayer || []; function gtag(){dataLayer.push(arguments);} gtag('js', new Date()); //- gtag('config', 'UA-71059016-1'); gtag('config', 'G-EPQ9202NVY'); </script> <title>PDB-101: Molecule of the Month: Ras Protein</title> <meta charset="utf-8"> <meta http-equiv="X-UA-Compatible" content="IE=edge"> <meta name="viewport" content="width=device-width, initial-scale=1"> <meta property="og:title" content="PDB101: Molecule of the Month: Ras Protein"> <meta property="og:description" content="Mutation of the growth-controlling ras protein can lead to cancer"> <meta property="og:image" content="https://cdn.rcsb.org/pdb101/motm/148/148-RasProtein_5p21.jpg"> <meta property="og:url" content="http://pdb101.rcsb.org/motm/148"> <meta property="og:site_name" content="RCSB: PDB-101"> <meta name="twitter:card" content="summary"> <meta 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= '/motm/jmol/?id=' + 148 console.log('src=' + src) $("#iframe").attr('src', src) jmolLoaded = true } } function clickJmolTab() { $('#jmol-tab').trigger('click') } // jmol script for legacy motms with multiple jmols var jmols = []; function loadIframeById(jmolId) { var jmol = jmols[jmolId - 1] if (jmol.loaded == false) { var src = '/motm/jmol/?id=' + 148 + '&jmolId=' + jmolId $("#iframe_" + jmolId).attr('src', src) jmol.loaded = true } } function clickJmolTab(i) { var j = i + 1 $('#jmol-tab-' + j).trigger('click') } </script> <div id="sub-navbar"> <div class="row hidden-print"> <div class="col-xs-12 col-sm-6 sub-navbar"> <h4>Molecule of the Month</h4> </div> <div class="col-xs-12 col-sm-6 text-right sub-navbar"> <table> <tr> <td onclick="location.href="/motm/motm-by-category"">By Category</td> <td onclick="location.href="/motm/motm-by-date"">By Date</td> <td onclick="location.href="/motm/motm-by-title"">By Title</td> </tr> </table> </div> </div> </div> <div data-elastic-include> <h1>Molecule of the Month: Ras Protein</h1> <p><i>Mutation of the growth-controlling ras protein can lead to cancer</i></p> <div> <div class="img-with-caption float-right"> <div class="img-with-caption-table"><img src="https://cdn.rcsb.org/pdb101/motm/148/148-RasProtein_5p21.jpg" alt="Ras protein with a non-hydrolyzable analogue of GTP." class="img-responsive"> <div class="img-caption"> <div style="margin-bottom:10px;"><i>Ras protein with a non-hydrolyzable analogue of GTP.</i></div><a href="https://cdn.rcsb.org/pdb101/motm/148/148-RasProtein_5p21.tif"><small>Download high quality TIFF image<span class="fa fa-cloud-download"></span></small></a> </div> </div> </div> <h4>Introduction</h4> <div>Cells are constantly sending messages, discussing nutrient levels and growth rates with other cells, and also managing the internal needs of the cell. These messages need to be clear and strong, so that they can be heard over the busy bustle inside the crowded cytoplasm. One way to strengthen signals is to link them to a process that is chemically irreversible, like the cleavage of ATP or GTP. The Ras protein, shown here from PDB entry <span class="rcsb_id_tag" title="Ras"><a href='http://www.rcsb.org/pdb/explore/explore.do?structureId=5p21' target='_blank'>5p21 <i class='fa fa-external-link'> </i></a></span>, uses this approach. It is normally in the "off" state, with GDP bound in the site. To turn it "on," the GDP is swapped for GTP. Then, after the signal is delivered, the GTP is cleaved to GDP and phosphate, turning the protein firmly off. It is particularly important that Ras has an unambiguous off state, because it is intimately involved in the control of cell growth.</div> <h4>Ras Oncogene</h4> <div>Oncogenes are genes that are closely linked to cancer, and the gene that encodes Ras was among the first to be discovered. Mutation of an oncogene changes the function of the encoded protein, creating the malignant properties that are needed for cancer to grow and spread. For instance, some oncogenes encode proteins involved in programmed cell death, such as <a HREF="/motm/31">p53 tumor suppressor</a>, and the oncogenic mutation allows the cancer cell to evade our powerful protections against abnormal growth. Ras is involved in the signals passed between cells that control the amount of growth that is allowed at any time. Cancer-causing mutation of Ras creates a form of the protein that is always on. This is a disaster, because the mutated Ras continually tells the cancer cells that it is okay to multiply, without the normal limits that control cell growth.</div> </div> <div class="clearfix"></div> <hr class="motm-hr"> <div> <h4>Ras Partners</h4> <div>Ras is at the middle of a complex signaling network that delivers messages about growth, and is assisted by many different proteins. GEF proteins (guanine nucleotide exchange factors), such as Sos-1 shown here (PDB entry <span class="rcsb_id_tag" title="Ras and Sos-1"><a href='http://www.rcsb.org/pdb/explore/explore.do?structureId=1bkd' target='_blank'>1bkd <i class='fa fa-external-link'> </i></a></span>), turn the Ras switch on. They wrench open the binding site, allowing GDP to exit. Once GTP has bound in the empty site, the on state interacts with effectors like PI3K纬 (PDB entry <span class="rcsb_id_tag" title="Ras and PI3Kgamma"><a href='http://www.rcsb.org/pdb/explore/explore.do?structureId=1he8' target='_blank'>1he8 <i class='fa fa-external-link'> </i></a></span>), a lipid kinase that phosphorylates lipids in the signaling network. Ras will then slowly break the GTP, but the process is accelerated by GAPs (GTPase-activating proteins), such as p120GAP shown here (PDB entry <span class="rcsb_id_tag" title="Ras and p120GAP"><a href='http://www.rcsb.org/pdb/explore/explore.do?structureId=1wq1' target='_blank'>1wq1 <i class='fa fa-external-link'> </i></a></span>).</div> <div class="img-with-caption float-left"> <div class="img-with-caption-table"><img src="https://cdn.rcsb.org/pdb101/motm/148/148-RasProtein_Ras.jpg" alt="Proteins involved in ras signalling, including lipid kinase PI3Kgamma (left), a GTPase-activating protein p120GAP (top right), and guanine nucleotide exchange factor Sos-1 (bottom right)." class="img-responsive"> <div class="img-caption"> <div style="margin-bottom:10px;"><i>Proteins involved in ras signalling, including lipid kinase PI3Kgamma (left), a GTPase-activating protein p120GAP (top right), and guanine nucleotide exchange factor Sos-1 (bottom right).</i></div><a href="https://cdn.rcsb.org/pdb101/motm/148/148-RasProtein_Ras.tif"><small>Download high quality TIFF image<span class="fa fa-cloud-download"></span></small></a> </div> </div> </div> </div> <div class="clearfix"></div> <hr class="motm-hr"> <h4>Exploring the Structure</h4> <div id="jmolTabs" class="jmolText"> <ul class="nav nav-tabs"> <li class="active"><a data-toggle="tab" href="#tabs-1">Image</a></li> <li><a id="jmol-tab" data-toggle="tab" href="#tabs-2" onclick="loadIframe();">JSmol</a></li> </ul> <div class="tab-content"> <div id="tabs-1" class="tab-pane active"> <h5>Ras Protein</h5> <div style="margin-top:0;" class="img-with-caption float-left"><img src="https://cdn.rcsb.org/pdb101/motm/148/5p21_4q21_jmol-jmol.jpg" onclick="clickJmolTab();" class="img-responsive"></div> <p>Many structures for Ras have been solved, showing the different conformational states in the signaling cycle. The two shown here capture Ras with GTP and GDP, in the on and off states (PDB entries <span class="rcsb_id_tag" title="Ras"><a href='http://www.rcsb.org/pdb/explore/explore.do?structureId=5p21' target='_blank'>5p21 <i class='fa fa-external-link'> </i></a></span> and <span class="rcsb_id_tag" title="Ras"><a href='http://www.rcsb.org/pdb/explore/explore.do?structureId=4q21' target='_blank'>4q21 <i class='fa fa-external-link'> </i></a></span>). Comparison of these structures revealed that two loops (in green) near the nucleotide change conformation. This is the signal that is recognized by the effector proteins that transmit the signal. Structures have also revealed the importance of glutamine 61, which positions a water molecule to perform the cleavage reaction. This glutamine is often mutated in cancer cells, so the GTP is never cleaved and the protein is always turned on. To see several other structures that show the action of this amino acid, click on the image for an interactive Jmol.</p> <div class="clearfix"></div> </div> <div id="tabs-2" class="tab-pane"> <iframe id="iframe" marginheight="0" marginwidth="0" scrolling="yes" frameborder="0" width="100%"></iframe> </div> </div> </div> <div class="row"> <div class="col-xs-12 col-sm-12 col-md-6"> <h4>Topics for Further Discussion</h4> <ol> <li>Structures for several mutants of Ras have been solved, including Ras with mutations of glutamine 61. You can use the Structure Comparison tool to compare these to the normal form of the protein.</li> <li>Many structures of Ras have been solved with modified forms of GTP, with nitrogen or carbon atoms connecting the phosphates. Why is this necessary?</li> </ol> <div data-elastic-exclude> <div class="col-xs-12 link-motm"> <h4>Related PDB-101 Resources</h4> <ul> <li>Browse <a href="/browse/cancer">Cancer</a></li> <li>Browse <a href="/browse/cellular-signaling">Cellular Signaling</a></li> </ul> </div> </div> </div> <div style="border-left:1px dashed #ddd;" class="col-xs-12 col-sm-12 col-md-6"> <h4>References</h4> <ol> <li>Y. Pylayeva-Gupta, E. Grabocka and D. Bar-Sagi (2011) Ras oncogenes: weaving a tumorigenic web. Nature Reviews Cancer 11, 761-774</li> <li>I. R. Vetter and A. Wittinghofer (2001) The guanine nucleotide-binding switch in three dimensions. Science 294, 1299-1304.</li> </ol> </div> </div> <hr class="motm-hr"> <p>April 2012, David Goodsell</p> <a href="http://doi.org/10.2210/rcsb_pdb/mom_2012_4">http://doi.org/10.2210/rcsb_pdb/mom_2012_4</a> </div> <div style="margin-top:20px;" class="row hidden-print"> <div class="col-xs-12"> <div class="panel panel-info"> <div class="panel-heading">About Molecule of the Month</div> <div class="panel-body"><small> The RCSB PDB Molecule of the Month by David S. Goodsell (The Scripps Research Institute and the RCSB PDB) presents short accounts on selected molecules from the Protein Data Bank. Each installment includes an introduction to the structure and function of the molecule, a discussion of the relevance of the molecule to human health and welfare, and suggestions for how visitors might view these structures and access further details.<a href="/motm/motm-about">More</a></small> </div> </div> </div> </div> <script> $('#iframe').load(function () { $(this).height($(this).contents().find('body').height() + 30); }); </script> </div> <div id="footer_main" class="hidden-print"> <div class="container"> <div class="row"> <div class="col-sm-12 col-md-7"> <p><strong>About PDB-101</strong></p> <p>Researchers around the globe make 3D structures freely available from the Protein Data Bank (PDB) archive. PDB-101 training materials help graduate students, postdoctoral scholars, and researchers use PDB data and RCSB PDB tools. 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PDB-101: Molecule of the Month: Ras Protein