View source for 6eie


==Ras guanine nucleotide exchange factor SOS2 (Rem-cdc25), with surface mutations==
<StructureSection load='6eie' size='340' side='right'caption='[[6eie]], [[Resolution|resolution]] 2.72&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6eie]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EIE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EIE FirstGlance]. <br>
</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SOS2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6eie FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eie OCA], [https://pdbe.org/6eie PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6eie RCSB], [https://www.ebi.ac.uk/pdbsum/6eie PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6eie ProSAT]</span></td></tr>
</table>
== Disease ==
[[https://www.uniprot.org/uniprot/SOS2_HUMAN SOS2_HUMAN]] Noonan syndrome. The disease is caused by mutations affecting the gene represented in this entry. 
== Function ==
[[https://www.uniprot.org/uniprot/SOS2_HUMAN SOS2_HUMAN]] Promotes the exchange of Ras-bound GDP by GTP.[UniProtKB:Q62245] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Since the late 1980s, mutations in the RAS genes have been recognized as major oncogenes with a high occurrence rate in human cancers. Such mutations reduce the ability of the small GTPase RAS to hydrolyze GTP, keeping this molecular switch in a constitutively active GTP-bound form that drives, unchecked, oncogenic downstream signaling. One strategy to reduce the levels of active RAS is to target guanine nucleotide exchange factors, which allow RAS to cycle from the inactive GDP-bound state to the active GTP-bound form. Here, we describe the identification of potent and cell-active small-molecule inhibitors which efficiently disrupt the interaction between KRAS and its exchange factor SOS1, a mode of action confirmed by a series of biophysical techniques. The binding sites, mode of action, and selectivity were elucidated using crystal structures of KRAS(G12C)-SOS1, SOS1, and SOS2. By preventing formation of the KRAS-SOS1 complex, these inhibitors block reloading of KRAS with GTP, leading to antiproliferative activity. The final compound 23 (BAY-293) selectively inhibits the KRAS-SOS1 interaction with an IC50 of 21 nM and is a valuable chemical probe for future investigations.

Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction.,Hillig RC, Sautier B, Schroeder J, Moosmayer D, Hilpmann A, Stegmann CM, Werbeck ND, Briem H, Boemer U, Weiske J, Badock V, Mastouri J, Petersen K, Siemeister G, Kahmann JD, Wegener D, Bohnke N, Eis K, Graham K, Wortmann L, von Nussbaum F, Bader B Proc Natl Acad Sci U S A. 2019 Feb 12;116(7):2551-2560. doi:, 10.1073/pnas.1812963116. Epub 2019 Jan 25. PMID:30683722<ref>PMID:30683722</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6eie" style="background-color:#fffaf0;"></div>

==See Also==
*[[Son of sevenless|Son of sevenless]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Hillig, R C]]
[[Category: Mastouri, J]]
[[Category: Moosmayer, D]]
[[Category: Gef]]
[[Category: Guanine exchange factor]]
[[Category: Signaling protein]]
[[Category: Sos2]]