5TUZ
Structure of human GLP SET-domain (EHMT1) in complex with inhibitor MS0124
Summary for 5TUZ
| Entry DOI | 10.2210/pdb5tuz/pdb |
| Related | 5TUY |
| Descriptor | Histone-lysine N-methyltransferase EHMT1, S-ADENOSYLMETHIONINE, ZINC ION, ... (6 entities in total) |
| Functional Keywords | methyl transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 62683.98 |
| Authors | Babault, N.,Xiong, Y.,Liu, J.,Jin, J. (deposition date: 2016-11-07, release date: 2017-02-22, Last modification date: 2023-10-04) |
| 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 Cited by 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: 28135087DOI: 10.1021/acs.jmedchem.6b01645 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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