5TUY

Structure of human G9a SET-domain (EHMT2) in complex with inhibitor MS0124

Summary for 5TUY

• Entry DOI: 10.2210/pdb5tuy/pdb
• Related: 5TUZ
• Descriptor: Histone-lysine N-methyltransferase EHMT2, ZINC ION, S-ADENOSYLMETHIONINE, ... (5 entities in total)
• Functional Keywords: methyl-transferase inhibitor complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 63877.07

Authors

Babault, N.,Xiong, Y.,Liu, J.,Jin, J. (deposition date: 2016-11-07, release date: 2017-02-22, Last modification date: 2024-10-30)

Primary citation

Xiong, Y.,Li, F.,Babault, N.,Dong, A.,Zeng, H.,Wu, H.,Chen, X.,Arrowsmith, C.H.,Brown, P.J.,Liu, J.,Vedadi, M.,Jin, J.
Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase.
J. Med. Chem., 60:1876-1891, 2017

PubMed Abstract: G9a-like protein (GLP) and G9a are highly homologous protein lysine methyltransferases (PKMTs) sharing approximately 80% sequence identity in their catalytic domains. GLP and G9a form a heterodimer complex and catalyze mono- and dimethylation of histone H3 lysine 9 and nonhistone substrates. Although they are closely related, GLP and G9a possess distinct physiological and pathophysiological functions. Thus, GLP or G9a selective small-molecule inhibitors are useful tools to dissect their distinct biological functions. We previously reported potent and selective G9a/GLP dual inhibitors including UNC0638 and UNC0642. Here we report the discovery of potent and selective GLP inhibitors including 4 (MS0124) and 18 (MS012), which are >30-fold and 140-fold selective for GLP over G9a and other methyltransferases, respectively. The cocrystal structures of GLP and G9a in the complex with either 4 or 18 displayed virtually identical binding modes and interactions, highlighting the challenges in structure-based design of selective inhibitors for either enzyme.

PubMed: 28135087
DOI: 10.1021/acs.jmedchem.6b01645

Experimental method

X-RAY DIFFRACTION (2.6 Å)