9EU0

Crystal structure of Danio rerio HDAC6 CD2 in complex with hydrolyzed DFMO-inhibitor (ITF7209)

これはPDB形式変換不可エントリーです。

9EU0 の概要

• エントリーDOI: 10.2210/pdb9eu0/pdb
• 分子名称: Histone deacetylase 6, ZINC ION, POTASSIUM ION, ... (6 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: 81925.34

構造登録者

Bebel, A.,Cellupica, E.,Stevenazzi, A.,Sandrone, G.,Vergani, B.,Caprini, G. (登録日: 2024-03-27, 公開日: 2024-12-04)

主引用文献

Cellupica, E.,Gaiassi, A.,Rocchio, I.,Rovelli, G.,Pomarico, R.,Sandrone, G.,Caprini, G.,Cordella, P.,Cukier, C.,Fossati, G.,Marchini, M.,Bebel, A.,Airoldi, C.,Palmioli, A.,Stevenazzi, A.,Steinkuhler, C.,Vergani, B.
Mechanistic and Structural Insights on Difluoromethyl-1,3,4-oxadiazole Inhibitors of HDAC6.
Int J Mol Sci, 25:-, 2024

PubMed Abstract: Histone deacetylase 6 (HDAC6) is increasingly recognized for its potential in targeted disease therapy. This study delves into the mechanistic and structural nuances of HDAC6 inhibition by difluoromethyl-1,3,4-oxadiazole (DFMO) derivatives, a class of non-hydroxamic inhibitors with remarkable selectivity and potency. Employing a combination of nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS) kinetic experiments, comprehensive enzymatic characterizations, and X-ray crystallography, we dissect the intricate details of the DFMO-HDAC6 interaction dynamics. More specifically, we find that the chemical structure of a DMFO and the binding mode of its difluoroacetylhydrazide derivative are crucial in determining the predominant hydrolysis mechanism. Our findings provide additional insights into two different mechanisms of DFMO hydrolysis, thus contributing to a better understanding of the HDAC6 inhibition by oxadiazoles in disease modulation and therapeutic intervention.

PubMed: 38892072
DOI: 10.3390/ijms25115885

実験手法

X-RAY DIFFRACTION (1.86 Å)