7avt: Difference between revisions
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<StructureSection load='7avt' size='340' side='right'caption='[[7avt]], [[Resolution|resolution]] 1.88Å' scene=''> | <StructureSection load='7avt' size='340' side='right'caption='[[7avt]], [[Resolution|resolution]] 1.88Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7avt]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[7avt]] 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=7AVT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AVT FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=S3T:~{N}-[(1~{R})-1-(3-aminophenyl)ethyl]-6,7-dimethoxy-2-methyl-quinazolin-4-amine'>S3T</scene> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.88Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=S3T:~{N}-[(1~{R})-1-(3-aminophenyl)ethyl]-6,7-dimethoxy-2-methyl-quinazolin-4-amine'>S3T</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=7avt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7avt OCA], [https://pdbe.org/7avt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7avt RCSB], [https://www.ebi.ac.uk/pdbsum/7avt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7avt 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=7avt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7avt OCA], [https://pdbe.org/7avt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7avt RCSB], [https://www.ebi.ac.uk/pdbsum/7avt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7avt ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == 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 == | == Function == | ||
[https://www.uniprot.org/uniprot/SOS1_HUMAN SOS1_HUMAN] Promotes the exchange of Ras-bound GDP by GTP. | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 22: | Line 21: | ||
</div> | </div> | ||
<div class="pdbe-citations 7avt" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 7avt" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Son of sevenless 3D structures|Son of sevenless 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Bader | [[Category: Bader G]] | ||
[[Category: Kessler | [[Category: Kessler D]] | ||
[[Category: Wolkerstorfer | [[Category: Wolkerstorfer B]] | ||
Latest revision as of 15:17, 1 February 2024
Crystal structure of SOS1 in complex with compound 7Crystal structure of SOS1 in complex with compound 7
Structural highlights
DiseaseSOS1_HUMAN Defects in SOS1 are the cause of gingival fibromatosis 1 (GGF1) [MIM: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.[1] Defects in SOS1 are the cause of Noonan syndrome type 4 (NS4) [MIM: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.[2] [3] [4] [5] [6] [7] [8] [9] FunctionSOS1_HUMAN Promotes the exchange of Ras-bound GDP by GTP. Publication Abstract from PubMedKRAS, the most common oncogenic driver in human cancers, is controlled and signals primarily through protein-protein interactions (PPIs). The interaction between KRAS and SOS1, crucial for the activation of KRAS, is a typical, challenging PPI with a large contact surface area and high affinity. Here, we report that the addition of only one atom placed between Y884(SOS1) and A73(KRAS) is sufficient to convert SOS1 activators into SOS1 inhibitors. We also disclose the discovery of BI-3406. Combination with the upstream EGFR inhibitor afatinib shows in vivo efficacy against KRAS(G13D) mutant colorectal tumor cells, demonstrating the utility of BI-3406 to probe SOS1 biology. These findings challenge the dogma that large molecules are required to disrupt challenging PPIs. Instead, a "foot in the door" approach, whereby single atoms or small functional groups placed between key PPI interactions, can lead to potent inhibitors even for challenging PPIs such as SOS1-KRAS. One Atom Makes All the Difference: Getting a Foot in the Door between SOS1 and KRAS.,Ramharter J, Kessler D, Ettmayer P, Hofmann MH, Gerstberger T, Gmachl M, Wunberg T, Kofink C, Sanderson M, Arnhof H, Bader G, Rumpel K, Zophel A, Schnitzer R, Bottcher J, O'Connell JC, Mendes RL, Richard D, Pototschnig N, Weiner I, Hela W, Hauer K, Haering D, Lamarre L, Wolkerstorfer B, Salamon C, Werni P, Munico-Martinez S, Meyer R, Kennedy MD, Kraut N, McConnell DB J Med Chem. 2021 Mar 15. doi: 10.1021/acs.jmedchem.0c01949. PMID:33719426[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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