化学
共晶
共价键
甲基转移酶
赖氨酸
小分子
半胱氨酸
生物化学
酶
分子
氨基酸
DNA
有机化学
甲基化
氢键
作者
Kyle V. Butler,Anqi Ma,Wenyu Yu,Fengling Li,W. Tempel,Nicolas Babault,Fábio Pittella Silva,Jason Shao,Junyi Wang,Minkui Luo,Masoud Vedadi,Peter J. Brown,C.H. Arrowsmith,Jian Jin
标识
DOI:10.1021/acs.jmedchem.6b01244
摘要
Selective inhibitors of protein lysine methyltransferases, including SET domain-containing protein 8 (SETD8), are highly desired, as only a fraction of these enzymes are associated with high-quality inhibitors. From our previously discovered SETD8 inhibitor, we developed a more potent analog and solved a cocrystal structure, which is the first crystal structure of SETD8 in complex with a small-molecule inhibitor. This cocrystal structure allowed the design of a covalent inhibitor of SETD8 (MS453), which specifically modifies a cysteine residue near the inhibitor binding site, has an IC50 value of 804 nM, reacts with SETD8 with near-quantitative yield, and is selective for SETD8 against 28 other methyltransferases. We also solved the crystal structure of the covalent inhibitor in complex with SETD8. This work provides atomic-level perspective on the inhibition of SETD8 by small molecules and will help identify high-quality chemical probes of SETD8.
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