8z7c
Structure of G9a in complex with compound 7i
Structural highlights
FunctionEHMT2_HUMAN Histone methyltransferase that specifically mono- and dimethylates 'Lys-9' of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin. H3K9me represents a specific tag for epigenetic transcriptional repression by recruiting HP1 proteins to methylated histones. Also mediates monomethylation of 'Lys-56' of histone H3 (H3K56me1) in G1 phase, leading to promote interaction between histone H3 and PCNA and regulating DNA replication. Also weakly methylates 'Lys-27' of histone H3 (H3K27me). Also required for DNA methylation, the histone methyltransferase activity is not required for DNA methylation, suggesting that these 2 activities function independently. Probably targeted to histone H3 by different DNA-binding proteins like E2F6, MGA, MAX and/or DP1. May also methylate histone H1. In addition to the histone methyltransferase activity, also methylates non-histone proteins: mediates dimethylation of 'Lys-373' of p53/TP53. Also methylates CDYL, WIZ, ACIN1, DNMT1, HDAC1, ERCC6, KLF12 and itself.[1] [2] [3] [4] [5] Publication Abstract from PubMedThe discovery and development of structurally distinct lysine methyltransferase G9a inhibitors have been the subject of intense research in epigenetics. Structure-based optimization was conducted, starting with the previously reported seed compound 7a and lead to the identification of a highly potent G9a inhibitor, compound 7i (IC(50) = 0.024 muM). X-ray crystallography for the ligand-protein interaction and kinetics study, along with surface plasmon resonance (SPR) analysis, revealed that compound 7i interacts with G9a in a unique binding mode. In addition, compound 7i caused attenuation of cellular H3K9me2 levels and induction of gamma-globin mRNA expression in HUDEP-2 cells in a dose-dependent manner. Structure-based development of novel substrate-type G9a inhibitors as epigenetic modulators for sickle cell disease treatment.,Nishigaya Y, Takase S, Sumiya T, Sato T, Niwa H, Sato S, Nakata A, Matsuoka S, Maemoto Y, Hashimoto N, Namie R, Honma T, Umehara T, Shirouzu M, Koyama H, Yoshida M, Ito A, Shirai F Bioorg Med Chem Lett. 2024 Sep 15;110:129856. doi: 10.1016/j.bmcl.2024.129856. , Epub 2024 Jun 22. PMID:38914346[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
