7O2P

Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 in complex with ITF3756

7O2P の概要

• エントリーDOI: 10.2210/pdb7o2p/pdb
• 分子名称: Histone deacetylase 6, ~{N}-oxidanyl-4-[(5-thiophen-2-yl-1,2,3,4-tetrazol-1-yl)methyl]benzamide, ZINC ION, ... (10 entities in total)
• 機能のキーワード: histone deacetylase, complex with hydroxamate inhibitor, hydrolase
• 由来する生物種: Danio rerio (Zebrafish, Brachydanio rerio)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 83436.03

構造登録者

Zrubek, K.,Sandrone, G.,Cukier, C.D.,Stevenazzi, A. (登録日: 2021-03-31, 公開日: 2021-10-27, 最終更新日: 2024-01-31)

主引用文献

Sandrone, G.,Cukier, C.D.,Zrubek, K.,Marchini, M.,Vergani, B.,Caprini, G.,Fossati, G.,Steinkuhler, C.,Stevenazzi, A.
Role of Fluorination in the Histone Deacetylase 6 (HDAC6) Selectivity of Benzohydroxamate-Based Inhibitors.
Acs Med.Chem.Lett., 12:1810-1817, 2021

PubMed Abstract: Nonselective histone deacetylase (HDAC) inhibitors show dose-limiting side effects due to the inhibition of multiple, essential HDAC subtypes that can be limited or prevented by restricting their selectivity. We herein report the crystal structures of zebrafish HDAC6 catalytic domain 2 (zHDAC6-CD2) in complex with the selective HDAC6 inhibitors ITF3756 and ITF3985 and shed light on the role of fluorination in the selectivity of benzohydroxamate-based structures over class I isoforms. The reason for the enhancement in the selectivity of the benzohydroxamate-based compounds is the presence of specific interactions between the fluorinated linker and the key residues Gly582, Ser531, and His614 of zHDAC6, which are hindered in class I HDAC isoforms by the presence of an Aspartate that replaces Ser531. These results can be used in the design and development of novel, highly selective HDAC6 inhibitors.

PubMed: 34795871
DOI: 10.1021/acsmedchemlett.1c00425

実験手法

X-RAY DIFFRACTION (1.9 Å)