5IX0

HDAC2 WITH LIGAND BRD7232

5IX0 の概要

• エントリーDOI: 10.2210/pdb5ix0/pdb
• 関連するPDBエントリー: 5IWG
• 分子名称: Histone deacetylase 2, ZINC ION, CALCIUM ION, ... (10 entities in total)
• 機能のキーワード: hdac histone deacetylase, hydrolase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : Q92769
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 131245.71

構造登録者

Steinbacher, S. (登録日: 2016-03-23, 公開日: 2016-08-31, 最終更新日: 2024-03-06)

主引用文献

Wagner, F.F.,Weiwer, M.,Steinbacher, S.,Schomburg, A.,Reinemer, P.,Gale, J.P.,Campbell, A.J.,Fisher, S.L.,Zhao, W.N.,Reis, S.A.,Hennig, K.M.,Thomas, M.,Muller, P.,Jefson, M.R.,Fass, D.M.,Haggarty, S.J.,Zhang, Y.L.,Holson, E.B.
Kinetic and structural insights into the binding of histone deacetylase 1 and 2 (HDAC1, 2) inhibitors.
Bioorg.Med.Chem., 24:4008-4015, 2016

PubMed Abstract: The structure-activity and structure-kinetic relationships of a series of novel and selective ortho-aminoanilide inhibitors of histone deacetylases (HDACs) 1 and 2 are described. Different kinetic and thermodynamic selectivity profiles were obtained by varying the moiety occupying an 11Å channel leading to the Zn(2+) catalytic pocket of HDACs 1 and 2, two paralogs with a high degree of structural similarity. The design of these novel inhibitors was informed by two ligand-bound crystal structures of truncated hHDAC2. BRD4884 and BRD7232 possess kinetic selectivity for HDAC1 versus HDAC2. We demonstrate that the binding kinetics of HDAC inhibitors can be tuned for individual isoforms in order to modulate target residence time while retaining functional activity and increased histone H4K12 and H3K9 acetylation in primary mouse neuronal cell culture assays. These chromatin modifiers, with tuned binding kinetic profiles, can be used to define the relation between target engagement requirements and the pharmacodynamic response of HDACs in different disease applications.

PubMed: 27377864
DOI: 10.1016/j.bmc.2016.06.040

実験手法

X-RAY DIFFRACTION (1.72 Å)