6ZW1

X-ray structure of Danio rerio histone deacetylase 6 (HDAC6) CD2 in complex with an inhibitor SW101

6ZW1 の概要

• エントリーDOI: 10.2210/pdb6zw1/pdb
• 分子名称: Histone deacetylase 6, ZINC ION, 1-[[4-(oxidanylcarbamoyl)phenyl]methyl]-3,4-dihydro-2~{H}-quinoline-6-carboxamide, ... (7 entities in total)
• 機能のキーワード: histone deacetylase, deacetylation, inhibitor, danio rerio, hydrolase
• 由来する生物種: Danio rerio (Zebrafish)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40668.44

構造登録者

Barinka, C.,Motlova, L.,Ustinova, K. (登録日: 2020-07-27, 公開日: 2021-08-04, 最終更新日: 2024-01-31)

主引用文献

Shen, S.,Picci, C.,Ustinova, K.,Benoy, V.,Kutil, Z.,Zhang, G.,Tavares, M.T.,Pavlicek, J.,Zimprich, C.A.,Robers, M.B.,Van Den Bosch, L.,Barinka, C.,Langley, B.,Kozikowski, A.P.
Tetrahydroquinoline-Capped Histone Deacetylase 6 Inhibitor SW-101 Ameliorates Pathological Phenotypes in a Charcot-Marie-Tooth Type 2A Mouse Model.
J.Med.Chem., 64:4810-4840, 2021

PubMed Abstract: Histone deacetylase 6 (HDAC6) is a promising therapeutic target for the treatment of neurodegenerative disorders. SW-100 (), a phenylhydroxamate-based HDAC6 inhibitor (HDAC6i) bearing a tetrahydroquinoline (THQ) capping group, is a highly potent and selective HDAC6i that was shown to be effective in mouse models of Fragile X syndrome and Charcot-Marie-Tooth disease type 2A (CMT2A). In this study, we report the discovery of a new THQ-capped HDAC6i, termed SW-101 (), that possesses excellent HDAC6 potency and selectivity, together with markedly improved metabolic stability and druglike properties compared to SW-100 (). X-ray crystallography data reveal the molecular basis of HDAC6 inhibition by SW-101 (). Importantly, we demonstrate that SW-101 () treatment elevates the impaired level of acetylated α-tubulin in the distal sciatic nerve, counteracts progressive motor dysfunction, and ameliorates neuropathic symptoms in a CMT2A mouse model bearing mutant 2. Taken together, these results bode well for the further development of SW-101 () as a disease-modifying HDAC6i.

PubMed: 33830764
DOI: 10.1021/acs.jmedchem.0c02210

実験手法

X-RAY DIFFRACTION (1.13 Å)