9mjl

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Current revision (09:29, 2 April 2025) (edit) (undo)
 
Line 1: Line 1:
-
'''Unreleased structure'''
 
-
The entry 9mjl is ON HOLD until Paper Publication
+
==SOS1 IN COMPLEX WITH AN INHIBITOR==
 +
<StructureSection load='9mjl' size='340' side='right'caption='[[9mjl]], [[Resolution|resolution]] 2.62&Aring;' scene=''>
 +
== Structural highlights ==
 +
<table><tr><td colspan='2'>[[9mjl]] is a 1 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=9MJL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9MJL 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]] 2.62&#8491;</td></tr>
 +
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1BME:6-[[(1~{R})-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]amino]-8-(oxan-4-yl)-1,2,3,4-tetrahydropyrido[4,3-c][2,7]naphthyridin-9-one'>A1BME</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=9mjl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9mjl OCA], [https://pdbe.org/9mjl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9mjl RCSB], [https://www.ebi.ac.uk/pdbsum/9mjl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9mjl ProSAT]</span></td></tr>
 +
</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 ==
 +
Small molecules that bind the Son of Sevenless 1 protein (SOS1), thereby preventing activation of RAS, have been widely pursued as a means for cell proliferation inhibition and antitumor activity. Guided by free-energy perturbation (FEP+) simulations, we discovered that two acidic residues on the perimeter of a known small molecule binding site on SOS1, E906 and E909, constitute a potency handle that can improve inhibitor affinity by as much as 750-fold when targeted with basic groups to form salt bridges, despite being solvent exposed. Structure-Activity Relationship (SAR) and X-ray crystallographic studies demonstrate that this effect is attributable to the electrostatic interaction between the protein and ligand. This interaction could be repurposed to create new SOS1 inhibitors, documenting its general utility for core exploration. Additional recent examples in the literature suggest that this phenomenon may be applicable to a number of target classes and are highlighted herein.
-
Authors: Bell, J.A.
+
Exploiting Solvent Exposed Salt-Bridge Interactions for the Discovery of Potent Inhibitors of SOS1 Using Free-Energy Perturbation Simulations.,Leffler AE, Houang EM, Gray F, Placzek AT, Ruvinsky AM, Bell JA, Wang H, Sun S, Svensson M, Greenwood JR, Frye LL, Igawa H, Atsriku C, Levinson AM ACS Med Chem Lett. 2025 Feb 28;16(3):444-453. doi: , 10.1021/acsmedchemlett.4c00602. eCollection 2025 Mar 13. PMID:40104782<ref>PMID:40104782</ref>
-
Description: SOS1 IN COMPLEX WITH AN INHIBITOR
+
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-
[[Category: Unreleased Structures]]
+
</div>
-
[[Category: Bell, J.A]]
+
<div class="pdbe-citations 9mjl" style="background-color:#fffaf0;"></div>
 +
== References ==
 +
<references/>
 +
__TOC__
 +
</StructureSection>
 +
[[Category: Homo sapiens]]
 +
[[Category: Large Structures]]
 +
[[Category: Bell JA]]

Current revision

SOS1 IN COMPLEX WITH AN INHIBITOR

PDB ID 9mjl

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/9mjl"
Personal tools