6d56

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'''Unreleased structure'''
 
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The entry 6d56 is ON HOLD
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==Ras:SOS:Ras in complex with a small molecule activator==
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<StructureSection load='6d56' size='340' side='right'caption='[[6d56]], [[Resolution|resolution]] 1.68&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6d56]] is a 3 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=6D56 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6D56 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.68&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=FVM:6-chloranyl-2-(2,6-diazaspiro[3.3]heptan-2-yl)-4-(3,5-dimethyl-1~{H}-pyrazol-4-yl)-1-[(4-fluoranyl-3,5-dimethyl-phenyl)methyl]benzimidazole'>FVM</scene>, <scene name='pdbligand=GNP:PHOSPHOAMINOPHOSPHONIC+ACID-GUANYLATE+ESTER'>GNP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6d56 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d56 OCA], [https://pdbe.org/6d56 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6d56 RCSB], [https://www.ebi.ac.uk/pdbsum/6d56 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6d56 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[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>
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== Function ==
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[https://www.uniprot.org/uniprot/SOS1_HUMAN SOS1_HUMAN] Promotes the exchange of Ras-bound GDP by GTP.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Son of sevenless homologue 1 (SOS1) is a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on RAS. In its active form, GTP-bound RAS is responsible for numerous critical cellular processes. Aberrant RAS activity is involved in ~30% of all human cancers; hence, SOS1 is an attractive therapeutic target for its role in modulating RAS activation. Here, we describe a new series of benzimidazole-derived SOS1 agonists. Using structure-guided design, we discovered small molecules that increase nucleotide exchange on RAS in vitro at sub-micromolar concentrations, bind to SOS1 with low double digit nanomolar affinity, rapidly enhance cellular RAS-GTP levels, and invoke biphasic signaling changes in phosphorylation of ERK 1/2. These compounds represent the most potent series of SOS1 agonists reported to date.
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Authors: Phan, J., Hodges, T., Fesik, S.W.
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Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS.,Hodges TR, Abbott JR, Little AJ, Sarkar D, Salovich JM, Howes J, Akan DT, Sai J, Arnold AL, Browning C, Burns MC, Sobolik T, Sun Q, Beesetty Y, Coker J, Scharn D, Stadtmueller H, Rossanese OW, Phan J, Waterson AG, McConnell DB, Fesik SW J Med Chem. 2018 Sep 11. doi: 10.1021/acs.jmedchem.8b01108. PMID:30205005<ref>PMID:30205005</ref>
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Description: Ras:SOS:Ras in complex with a small molecule activator
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Fesik, S.W]]
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<div class="pdbe-citations 6d56" style="background-color:#fffaf0;"></div>
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[[Category: Phan, J]]
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[[Category: Hodges, T]]
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==See Also==
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*[[GTPase Hras 3D structures|GTPase Hras 3D structures]]
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*[[Son of sevenless 3D structures|Son of sevenless 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Fesik SW]]
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[[Category: Hodges T]]
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[[Category: Phan J]]

Current revision

Ras:SOS:Ras in complex with a small molecule activator

PDB ID 6d56

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