5VSC

Structure of human G9a SET-domain (EHMT2) in complex with inhibitor 13

5VSC の概要

• エントリーDOI: 10.2210/pdb5vsc/pdb
• 関連するPDBエントリー: 5VSD 5VSE 5VSF
• 分子名称: Histone-lysine N-methyltransferase EHMT2, ZINC ION, S-ADENOSYLMETHIONINE, ... (5 entities in total)
• 機能のキーワード: protein-small molecule inhibitor complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : Q96KQ7
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 65533.10

構造登録者

Babault, N.,Xiong, Y.,Liu, J.,Jin, J. (登録日: 2017-05-11, 公開日: 2017-07-12, 最終更新日: 2023-10-04)

主引用文献

Xiong, Y.,Li, F.,Babault, N.,Wu, H.,Dong, A.,Zeng, H.,Chen, X.,Arrowsmith, C.H.,Brown, P.J.,Liu, J.,Vedadi, M.,Jin, J.
Structure-activity relationship studies of G9a-like protein (GLP) inhibitors.
Bioorg. Med. Chem., 25:4414-4423, 2017

PubMed Abstract: Given the high homology between the protein lysine methyltransferases G9a-like protein (GLP) and G9a, it has been challenging to develop potent and selective inhibitors for either enzyme. Recently, we reported two quinazoline compounds, MS0124 and MS012, as GLP selective inhibitors. To further investigate the structure-activity relationships (SAR) of the quinazoline scaffold, we designed and synthesized a range of analogs bearing different 2-amino substitutions and evaluated their inhibition potencies against both GLP and G9a. These studies led to the identification of two new GLP selective inhibitors, 13 (MS3748) and 17 (MS3745), with 59- and 65-fold higher potency for GLP over G9a, which were confirmed by isothermal titration calorimetry (ITC). Crystal structures of GLP and G9a in complex with 13 and 17 provide insight into the interactions of the inhibitors with both proteins. In addition, we generated GLP selective inhibitors bearing a quinoline core instead of the quinazoline core.

PubMed: 28662962
DOI: 10.1016/j.bmc.2017.06.021

実験手法

X-RAY DIFFRACTION (1.4 Å)