8A8Z

Crystal structure of Danio rerio HDAC6 CD2 in complex with in situ enzymatically hydrolyzed DFMO-based ITF5924

8A8Z の概要

• エントリーDOI: 10.2210/pdb8a8z/pdb
• 分子名称: Histone deacetylase 6, 4-[[4-[4-(imidazolidin-2-ylideneamino)phenyl]-1,2,3-triazol-1-yl]methyl]benzohydrazide, ZINC ION, ... (5 entities in total)
• 機能のキーワード: histone deacetylase, complex with hydrazide, hydrolase, non-hydroxamate zinc binding group, mechanism-based inhibitor
• 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: 81725.11

構造登録者

Zrubek, K.,Sandrone, G.,Cukier, C.D.,Stevenazzi, A. (登録日: 2022-06-27, 公開日: 2023-01-25, 最終更新日: 2024-02-07)

主引用文献

Cellupica, E.,Caprini, G.,Cordella, P.,Cukier, C.,Fossati, G.,Marchini, M.,Rocchio, I.,Sandrone, G.,Vanoni, M.A.,Vergani, B.,Zrubek, K.,Stevenazzi, A.,Steinkuhler, C.
Difluoromethyl-1,3,4-oxadiazoles are slow-binding substrate analog inhibitors of histone deacetylase 6 with unprecedented isotype selectivity.
J.Biol.Chem., 299:102800-102800, 2022

PubMed Abstract: Histone deacetylase 6 (HDAC6) is an attractive drug development target because of its role in the immune response, neuropathy, and cancer. Knockout mice develop normally and have no apparent phenotype, suggesting that selective inhibitors should have an excellent therapeutic window. Unfortunately, current HDAC6 inhibitors have only moderate selectivity and may inhibit other HDAC subtypes at high concentrations, potentially leading to side effects. Recently, substituted oxadiazoles have attracted attention as a promising novel HDAC inhibitor chemotype, but their mechanism of action is unknown. Here, we show that compounds containing a difluoromethyl-1,3,4-oxadiazole (DFMO) moiety are potent and single-digit nanomolar inhibitors with an unprecedented greater than 10-fold selectivity for HDAC6 over all other HDAC subtypes. By combining kinetics, X-ray crystallography, and mass spectrometry, we found that DFMO derivatives are slow-binding substrate analogs of HDAC6 that undergo an enzyme-catalyzed ring opening reaction, forming a tight and long-lived enzyme-inhibitor complex. The elucidation of the mechanism of action of DFMO derivatives paves the way for the rational design of highly selective inhibitors of HDAC6 and possibly of other HDAC subtypes as well with potentially important therapeutic implications.

PubMed: 36528061
DOI: 10.1016/j.jbc.2022.102800

実験手法

X-RAY DIFFRACTION (1.6 Å)