7T7L

Structure of human G9a SET-domain (EHMT2) in complex with covalent inhibitor (Compound 1)

Summary for 7T7L

• Entry DOI: 10.2210/pdb7t7l/pdb
• Descriptor: Histone-lysine N-methyltransferase EHMT2, ZINC ION, S-ADENOSYLMETHIONINE, ... (6 entities in total)
• Functional Keywords: g9a, covalent inhibitor, gene regulation
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 135052.62

Authors

Park, K.-S.,Kumar, P. (deposition date: 2021-12-15, release date: 2022-07-06, Last modification date: 2024-10-16)

Primary citation

Park, K.S.,Xiong, Y.,Yim, H.,Velez, J.,Babault, N.,Kumar, P.,Liu, J.,Jin, J.
Discovery of the First-in-Class G9a/GLP Covalent Inhibitors.
J.Med.Chem., 65:10506-10522, 2022

PubMed Abstract: The highly homologous protein lysine methyltransferases G9a and GLP, which catalyze mono- and dimethylation of histone H3 lysine 9 (H3K9), have been implicated in various human diseases. To investigate functions of G9a and GLP in human diseases, we and others reported several noncovalent reversible small-molecule inhibitors of G9a and GLP. Here, we report the discovery of the first-in-class G9a/GLP covalent irreversible inhibitors, and (MS8511), by targeting a cysteine residue at the substrate binding site. We characterized these covalent inhibitors in enzymatic, mass spectrometry based and cellular assays and using X-ray crystallography. Compared to the noncovalent G9a/GLP inhibitor UNC0642, covalent inhibitor displayed improved potency in enzymatic and cellular assays. Interestingly, compound also displayed potential kinetic preference for covalently modifying G9a over GLP. Collectively, compound could be a useful chemical tool for studying the functional roles of G9a and GLP by covalently modifying and inhibiting these methyltransferases.

PubMed: 35763668
DOI: 10.1021/acs.jmedchem.2c00652

Experimental method

X-RAY DIFFRACTION (2.2 Å)