5YJO

Crystal structure of SmyD3 in complex with covalent inhibitor 4

5YJO の概要

• エントリーDOI: 10.2210/pdb5yjo/pdb
• 分子名称: Histone-lysine N-methyltransferase SMYD3, ZINC ION, propyl (3~{S})-4-[[(6~{R})-6-(aminomethyl)-5,6,7,8-tetrahydroacridin-3-yl]carbonyl]-3-methyl-piperazine-1-carboxylate, ... (5 entities in total)
• 機能のキーワード: covalent inhibitor, methyltransferase, methyltransferase inhibitor, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 49621.66

構造登録者

Baburajendran, N.,Anna E, J. (登録日: 2017-10-11, 公開日: 2018-10-17, 最終更新日: 2024-11-06)

主引用文献

Huang, C.,Liew, S.S.,Lin, G.R.,Poulsen, A.,Ang, M.J.Y.,Chia, B.C.S.,Chew, S.Y.,Kwek, Z.P.,Wee, J.L.K.,Ong, E.H.,Retna, P.,Baburajendran, N.,Li, R.,Yu, W.,Koh-Stenta, X.,Ngo, A.,Manesh, S.,Fulwood, J.,Ke, Z.,Chung, H.H.,Sepramaniam, S.,Chew, X.H.,Dinie, N.,Lee, M.A.,Chew, Y.S.,Low, C.B.,Pendharkar, V.,Manoharan, V.,Vuddagiri, S.,Sangthongpitag, K.,Joy, J.,Matter, A.,Hill, J.,Keller, T.H.,Foo, K.
Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3.
Acs Med.Chem.Lett., 10:978-984, 2019

PubMed Abstract: SMYD3 is a histone methyltransferase that regulates gene transcription, and its overexpression is associated with multiple human cancers. A novel class of tetrahydroacridine compounds which inhibit SMYD3 through a covalent mechanism of action is identified. Optimization of these irreversible inhibitors resulted in the discovery of 4-chloroquinolines, a new class of covalent warheads. Tool compound exhibits high potency by inhibiting SMYD3's enzymatic activity and showing antiproliferative activity against HepG2 in 3D cell culture. Our findings suggest that covalent inhibition of SMYD3 may have an impact on SMYD3 biology by affecting expression levels, and this warrants further exploration.

PubMed: 31223458
DOI: 10.1021/acsmedchemlett.9b00170

実験手法

X-RAY DIFFRACTION (2.135 Å)