6qpl

Crystal structure of Spindlin1 in complex with the inhibitor MS31

spinqualitylabelsall models 6qpl, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6qpl is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.6Å Ligands: DMS, GLY, GOL, JC5, MPD, PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function SPIN1_HUMAN May play a role in cell-cycle regulation during the transition from gamete to embryo (By similarity). Publication Abstract from PubMed By screening an epigenetic compound library, we identified that UNC0638, a highly potent inhibitor of the histone methyltransferases G9a and GLP, was a weak inhibitor of SPIN1 (Spindlin 1), a methyllysine reader protein. Our optimization of this weak hit resulted in the discovery of a potent, selective and cell-active SPIN1 inhibitor, compound 3 (MS31). Compound 3 potently inhibited binding of trimethyllysine-containing peptides to SPIN1, displayed high binding affinity, was highly selective for SPIN1 over other epigenetic readers and writers, directly engaged SPIN1 in cells, and was not toxic to non-tumorigenic cells. The crystal structure of the SPIN1-compound 3 complex indicated that it selectively binds Tudor domain II of SPIN1. We also designed a structurally similar but inactive compound 4 (MS31N) as a negative control. Our results have demonstrated for the first time that potent, selective and cell-active fragment-like inhibitors can be generated by targeting a single Tudor domain. Discovery of a Potent and Selective Fragment-like Inhibitor of Methyllysine Reader Protein Spindlin 1 (SPIN1).,Xiong Y, Greschik H, Johansson C, Seifert L, Bacher J, Park KS, Babault N, Martini ML, Fagan V, Li F, Chau I, Christott T, Dilworth D, Barsyte-Lovejoy D, Vedadi M, Arrowsmith CH, Brennan PE, Fedorov O, Jung M, Farnie G, Liu J, Oppermann UCT, Schule R, Jin J J Med Chem. 2019 Jul 1. doi: 10.1021/acs.jmedchem.9b00522. PMID:31260300 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Spindlin

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