6QPL

Crystal structure of Spindlin1 in complex with the inhibitor MS31

Summary for 6QPL

• Entry DOI: 10.2210/pdb6qpl/pdb
• Descriptor: Spindlin-1, (4S)-2-METHYL-2,4-PENTANEDIOL, DIMETHYL SULFOXIDE, ... (8 entities in total)
• Functional Keywords: epigenetics, tudor domain, methyl-lysine, methyl-arginine, cell cycle
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 26495.97

Authors

Johansson, C.,Krojer, T.,Xiong, Y.,Jin, J.,Arrowsmith, C.H.,Bountra, C.,Edwards, A.,Oppermann, U.C.T. (deposition date: 2019-02-14, release date: 2019-07-17, Last modification date: 2024-01-24)

Primary citation

Xiong, Y.,Greschik, H.,Johansson, C.,Seifert, L.,Bacher, J.,Park, K.S.,Babault, N.,Martini, M.,Fagan, V.,Li, F.,Chau, I.,Christott, T.,Dilworth, D.,Barsyte-Lovejoy, D.,Vedadi, M.,Arrowsmith, C.H.,Brennan, P.,Fedorov, O.,Jung, M.,Farnie, G.,Liu, J.,Oppermann, U.,Schule, R.,Jin, J.
Discovery of a Potent and Selective Fragment-like Inhibitor of Methyllysine Reader Protein Spindlin 1 (SPIN1).
J.Med.Chem., 62:8996-9007, 2019

PubMed Abstract: 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 (MS31). Compound 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 nontumorigenic cells. The crystal structure of the SPIN1-compound complex indicated that it selectively binds tudor domain II of SPIN1. We also designed a structurally similar but inactive compound (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.

PubMed: 31260300
DOI: 10.1021/acs.jmedchem.9b00522

Experimental method

X-RAY DIFFRACTION (1.6 Å)