6eie

Ras guanine nucleotide exchange factor SOS2 (Rem-cdc25), with surface mutations

spinqualitylabelsall models 6eie, resolution 2.72Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6eie is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Gene: SOS2 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [SOS2_HUMAN] Noonan syndrome. The disease is caused by mutations affecting the gene represented in this entry. Function [SOS2_HUMAN] Promotes the exchange of Ras-bound GDP by GTP.[UniProtKB:Q62245] Publication Abstract from PubMed Since the late 1980s, mutations in the RAS genes have been recognized as major oncogenes with a high occurrence rate in human cancers. Such mutations reduce the ability of the small GTPase RAS to hydrolyze GTP, keeping this molecular switch in a constitutively active GTP-bound form that drives, unchecked, oncogenic downstream signaling. One strategy to reduce the levels of active RAS is to target guanine nucleotide exchange factors, which allow RAS to cycle from the inactive GDP-bound state to the active GTP-bound form. Here, we describe the identification of potent and cell-active small-molecule inhibitors which efficiently disrupt the interaction between KRAS and its exchange factor SOS1, a mode of action confirmed by a series of biophysical techniques. The binding sites, mode of action, and selectivity were elucidated using crystal structures of KRAS(G12C)-SOS1, SOS1, and SOS2. By preventing formation of the KRAS-SOS1 complex, these inhibitors block reloading of KRAS with GTP, leading to antiproliferative activity. The final compound 23 (BAY-293) selectively inhibits the KRAS-SOS1 interaction with an IC50 of 21 nM and is a valuable chemical probe for future investigations. Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction.,Hillig RC, Sautier B, Schroeder J, Moosmayer D, Hilpmann A, Stegmann CM, Werbeck ND, Briem H, Boemer U, Weiske J, Badock V, Mastouri J, Petersen K, Siemeister G, Kahmann JD, Wegener D, Bohnke N, Eis K, Graham K, Wortmann L, von Nussbaum F, Bader B Proc Natl Acad Sci U S A. 2019 Feb 12;116(7):2551-2560. doi:, 10.1073/pnas.1812963116. Epub 2019 Jan 25. PMID:30683722 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Son of sevenless

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