8GD4

Crystal Structure of Danio rerio histone deacetylase 6 catalytic domain 2 complexed with DMFO Inhibitor 6

8GD4 の概要

• エントリーDOI: 10.2210/pdb8gd4/pdb
• 分子名称: Hdac6 protein, 2-(benzylamino)-N'-(difluoroacetyl)pyrimidine-5-carbohydrazide, ZINC ION, ... (5 entities in total)
• 機能のキーワード: hydrolase, histone deacetylase, inhibitor, metallohydrolase
• 由来する生物種: Danio rerio (zebrafish)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 81500.74

構造登録者

Watson, P.R.,Craigin, A.D.,Christianson, D.W. (登録日: 2023-03-03, 公開日: 2023-10-04, 最終更新日: 2023-10-25)

主引用文献

Konig, B.,Watson, P.R.,Ressing, N.,Cragin, A.D.,Schaker-Hubner, L.,Christianson, D.W.,Hansen, F.K.
Difluoromethyl-1,3,4-oxadiazoles Are Selective, Mechanism-Based, and Essentially Irreversible Inhibitors of Histone Deacetylase 6 .
J.Med.Chem., 66:13821-13837, 2023

PubMed Abstract: Histone deacetylase (HDAC6) is an important drug target in oncological and non-oncological diseases. Most available HDAC6 inhibitors (HDAC6i) utilize hydroxamic acids as a zinc-binding group, which limits therapeutic opportunities due to its genotoxic potential. Recently, difluoromethyl-1,3,4-oxadiazoles (DFMOs) were reported as potent and selective HDAC6i but their mode of inhibition remained enigmatic. Herein, we report that DFMOs act as mechanism-based and essentially irreversible HDAC6i. Biochemical data confirm that DFMO is a tight-binding HDAC6i capable of inhibiting HDAC6 via a two-step slow-binding mechanism. Crystallographic and mechanistic experiments suggest that the attack of by the zinc-bound water at the sp carbon closest to the difluoromethyl moiety followed by a subsequent ring opening of the oxadiazole yields deprotonated difluoroacetylhydrazide as active species. The strong anionic zinc coordination of and the binding of the difluoromethyl moiety in the P571 pocket finally result in an essentially irreversible inhibition of HDAC6.

PubMed: 37782298
DOI: 10.1021/acs.jmedchem.3c01345

実験手法

X-RAY DIFFRACTION (2 Å)