7T7M
Structure of human GLP SET-domain (EHMT1) in complex with covalent inhibitor (Compound 1)
Summary for 7T7M
| Entry DOI | 10.2210/pdb7t7m/pdb |
| Descriptor | Histone-lysine N-methyltransferase EHMT1, ZINC ION, N-(6-methoxy-4-{[1-(propan-2-yl)piperidin-4-yl]amino}-7-[3-(pyrrolidin-1-yl)propoxy]quinazolin-2-yl)prop-2-enamide, ... (5 entities in total) |
| Functional Keywords | glp, covalent inhibitor, gene regulation, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 134932.52 |
| Authors | Park, K.-S.,Kumar, P. (deposition date: 2021-12-15, release date: 2022-07-06, Last modification date: 2024-11-06) |
| 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 Cited by 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: 35763668DOI: 10.1021/acs.jmedchem.2c00652 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.85 Å) |
Structure validation
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