7JOM

Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 complexed with TO-317

7JOM の概要

• エントリーDOI: 10.2210/pdb7jom/pdb
• 分子名称: Hdac6 protein, N-hydroxy-4-({[(pyridin-3-yl)methyl][(2,3,4,5-tetrafluorophenyl)sulfonyl]amino}methyl)benzamide, 1,2-ETHANEDIOL, ... (7 entities in total)
• 機能のキーワード: hydrolase, histone deacetylase, inhibitor, metallohydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase 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: 82206.40

構造登録者

Watson, P.R.,Christianson, D.W. (登録日: 2020-08-06, 公開日: 2021-06-16, 最終更新日: 2023-10-18)

主引用文献

Olaoye, O.O.,Watson, P.R.,Nawar, N.,Geletu, M.,Sedighi, A.,Bukhari, S.,Raouf, Y.S.,Manaswiyoungkul, P.,Erdogan, F.,Abdeldayem, A.,Cabral, A.D.,Hassan, M.M.,Toutah, K.,Shouksmith, A.E.,Gawel, J.M.,Israelian, J.,Radu, T.B.,Kachhiyapatel, N.,de Araujo, E.D.,Christianson, D.W.,Gunning, P.T.
Unique Molecular Interaction with the Histone Deacetylase 6 Catalytic Tunnel: Crystallographic and Biological Characterization of a Model Chemotype.
J.Med.Chem., 64:2691-2704, 2021

PubMed Abstract: Histone deacetylase 6 (HDAC6) is involved in multiple regulatory processes, ranging from cellular stress to intracellular transport. Inhibition of aberrant HDAC6 activity in several cancers and neurological diseases has been shown to be efficacious in both preclinical and clinical studies. While selective HDAC6 targeting has been pursued as an alternative to pan-HDAC drugs, identifying truly selective molecular templates has not been trivial. Herein, we report a structure-activity relationship study yielding , which potently binds HDAC6 catalytic domain 2 ( = 0.7 nM) and inhibits the enzyme function (IC = 2 nM). exhibits 158-fold selectivity for HDAC6 over other HDAC isozymes by binding the catalytic Zn and, uniquely, making a never seen before direct hydrogen bond with the Zn coordinating residue, His614. This novel structural motif targeting the second-sphere His614 interaction, observed in a 1.84 Å resolution crystal structure with HDAC6 from zebrafish, can provide new pharmacophores for identifying enthalpically driven, high-affinity, HDAC6-selective inhibitors.

PubMed: 33576627
DOI: 10.1021/acs.jmedchem.0c01922

実験手法

X-RAY DIFFRACTION (1.84 Å)