7uks
From Proteopedia
(Difference between revisions)
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| - | ==Crystal structure of SOS1 with | + | ==Crystal structure of SOS1 with phthalazine inhibitor bound (compound 15)== |
| - | <StructureSection load='7uks' size='340' side='right'caption='[[7uks]]' scene=''> | + | <StructureSection load='7uks' size='340' side='right'caption='[[7uks]], [[Resolution|resolution]] 2.29Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7UKS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UKS FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7uks]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7UKS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UKS FirstGlance]. <br> |
| - | </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=7uks FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7uks OCA], [https://pdbe.org/7uks PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7uks RCSB], [https://www.ebi.ac.uk/pdbsum/7uks PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7uks ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NL0:4-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-7-(piperazin-1-yl)phthalazin-1-amine'>NL0</scene></td></tr> |
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7ukr|7ukr]]</div></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=7uks FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7uks OCA], [https://pdbe.org/7uks PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7uks RCSB], [https://www.ebi.ac.uk/pdbsum/7uks PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7uks ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Disease == | ||
| + | [[https://www.uniprot.org/uniprot/SOS1_HUMAN SOS1_HUMAN]] Defects in SOS1 are the cause of gingival fibromatosis 1 (GGF1) [MIM:[https://omim.org/entry/135300 135300]]; also known as GINGF1. Gingival fibromatosis is a rare overgrowth condition characterized by a benign, slowly progressive, nonhemorrhagic, fibrous enlargement of maxillary and mandibular keratinized gingiva. GGF1 is usually transmitted as an autosomal dominant trait, although sporadic cases are common.<ref>PMID:11868160</ref> Defects in SOS1 are the cause of Noonan syndrome type 4 (NS4) [MIM:[https://omim.org/entry/610733 610733]]. NS4 is an autosomal dominant disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. It is a genetically heterogeneous and relatively common syndrome, with an estimated incidence of 1 in 1000-2500 live births. Rarely, NS4 is associated with juvenile myelomonocytic leukemia (JMML). SOS1 mutations engender a high prevalence of pulmonary valve disease; atrial septal defects are less common.<ref>PMID:17143285</ref> <ref>PMID:17143282</ref> <ref>PMID:19020799</ref> <ref>PMID:19438935</ref> <ref>PMID:20683980</ref> <ref>PMID:20673819</ref> <ref>PMID:19953625</ref> <ref>PMID:21387466</ref> | ||
| + | == Function == | ||
| + | [[https://www.uniprot.org/uniprot/SOS1_HUMAN SOS1_HUMAN]] Promotes the exchange of Ras-bound GDP by GTP. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | SOS1 is one of the major guanine nucleotide exchange factors that regulates the ability of KRAS to cycle through its "on" and "off" states. Disrupting the SOS1:KRAS(G12C) protein-protein interaction (PPI) can increase the proportion of GDP-loaded KRAS(G12C), providing a strong mechanistic rationale for combining inhibitors of the SOS1:KRAS complex with inhibitors like MRTX849 that target GDP-loaded KRAS(G12C). In this report, we detail the design and discovery of MRTX0902 horizontal line a potent, selective, brain-penetrant, and orally bioavailable SOS1 binder that disrupts the SOS1:KRAS(G12C) PPI. Oral administration of MRTX0902 in combination with MRTX849 results in a significant increase in antitumor activity relative to that of either single agent, including tumor regressions in a subset of animals in the MIA PaCa-2 tumor mouse xenograft model. | ||
| + | |||
| + | Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the SOS1:KRAS Protein-Protein Interaction.,Ketcham JM, Haling J, Khare S, Bowcut V, Briere DM, Burns AC, Gunn RJ, Ivetac A, Kuehler J, Kulyk S, Laguer J, Lawson JD, Moya K, Nguyen N, Rahbaek L, Saechao B, Smith CR, Sudhakar N, Thomas NC, Vegar L, Vanderpool D, Wang X, Yan L, Olson P, Christensen JG, Marx MA J Med Chem. 2022 Jul 14. doi: 10.1021/acs.jmedchem.2c00741. PMID:35833726<ref>PMID:35833726</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7uks" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Gunn | + | [[Category: Gunn, R J]] |
| - | [[Category: Ketcham | + | [[Category: Ketcham, J M]] |
| - | [[Category: Lawson | + | [[Category: Lawson, J D]] |
| - | [[Category: Marx | + | [[Category: Marx, M A]] |
| + | [[Category: Kra]] | ||
| + | [[Category: Protein-protein interaction]] | ||
| + | [[Category: Ra]] | ||
| + | [[Category: Signaling protein]] | ||
| + | [[Category: Signaling protein-inhibitor complex]] | ||
| + | [[Category: Sos1]] | ||
Revision as of 05:03, 3 August 2022
Crystal structure of SOS1 with phthalazine inhibitor bound (compound 15)
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