7tlg
From Proteopedia
(Difference between revisions)
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<table><tr><td colspan='2'>[[7tlg]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TLG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TLG FirstGlance]. <br> | <table><tr><td colspan='2'>[[7tlg]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TLG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TLG FirstGlance]. <br> | ||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8000072Å</td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8000072Å</td></tr> | ||
| - | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=I7H:( | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=I7H:(3~{R},4~{R})-1-[7-(8-chloranylnaphthalen-1-yl)-8-fluoranyl-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)pyrido[4,3-d]pyrimidin-4-yl]-3-oxidanyl-piperidine-4-carbaldehyde'>I7H</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></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=7tlg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tlg OCA], [https://pdbe.org/7tlg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tlg RCSB], [https://www.ebi.ac.uk/pdbsum/7tlg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tlg ProSAT]</span></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=7tlg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tlg OCA], [https://pdbe.org/7tlg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tlg RCSB], [https://www.ebi.ac.uk/pdbsum/7tlg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tlg ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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Drugs that directly impede the function of driver oncogenes offer exceptional efficacy and a therapeutic window. The recently approved mutant selective small-molecule cysteine-reactive covalent inhibitor of the G12C mutant of K-Ras, sotorasib, provides a case in point. KRAS is the most frequently mutated proto-oncogene in human cancer, yet despite success targeting the G12C allele, targeted therapy for other hotspot mutants of KRAS has not been described. Here we report the discovery of small molecules that covalently target a G12S somatic mutation in K-Ras and suppress its oncogenic signaling. We show that these molecules are active in cells expressing K-Ras(G12S) but spare the wild-type protein. Our results provide a path to targeting a second somatic mutation in the oncogene KRAS by overcoming the weak nucleophilicity of an acquired serine residue. The chemistry we describe may serve as a basis for the selective targeting of other unactivated serines. | Drugs that directly impede the function of driver oncogenes offer exceptional efficacy and a therapeutic window. The recently approved mutant selective small-molecule cysteine-reactive covalent inhibitor of the G12C mutant of K-Ras, sotorasib, provides a case in point. KRAS is the most frequently mutated proto-oncogene in human cancer, yet despite success targeting the G12C allele, targeted therapy for other hotspot mutants of KRAS has not been described. Here we report the discovery of small molecules that covalently target a G12S somatic mutation in K-Ras and suppress its oncogenic signaling. We show that these molecules are active in cells expressing K-Ras(G12S) but spare the wild-type protein. Our results provide a path to targeting a second somatic mutation in the oncogene KRAS by overcoming the weak nucleophilicity of an acquired serine residue. The chemistry we describe may serve as a basis for the selective targeting of other unactivated serines. | ||
| - | Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S).,Zhang Z, Guiley KZ, Shokat KM Nat Chem Biol. 2022 | + | Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S).,Zhang Z, Guiley KZ, Shokat KM Nat Chem Biol. 2022 Nov;18(11):1177-1183. doi: 10.1038/s41589-022-01065-9. Epub , 2022 Jul 21. PMID:35864332<ref>PMID:35864332</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Current revision
Crystal Structure of small molecule beta-lactone 5 covalently bound to K-Ras(G12S)
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