9CBK

Crystal Structure of Danio rerio Histone Deacetylase 6 in Complex with p-Aminomethyl Phenylthioketone

これはPDB形式変換不可エントリーです。

9CBK の概要

• エントリーDOI: 10.2210/pdb9cbk/pdb
• 分子名称: Hdac6 protein, 1-[4-(aminomethyl)phenyl]-2-sulfanylethan-1-one, 1,2-ETHANEDIOL, ... (6 entities in total)
• 機能のキーワード: hydrolase, histone deacetylase, inhibitor, metallohydrolase, hydrolase-inhibitor complex, 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: 81468.96

構造登録者

Goulart Stollmaier, J.,Watson, P.R.,Christianson, D.W. (登録日: 2024-06-19, 公開日: 2024-09-11, 最終更新日: 2024-10-30)

主引用文献

Goulart Stollmaier, J.,Watson, P.R.,Christianson, D.W.
Design, Synthesis, and Structural Evaluation of Acetylated Phenylthioketone Inhibitors of HDAC10.
Acs Med.Chem.Lett., 15:1715-1723, 2024

PubMed Abstract: Histone deacetylase 10 (HDAC10) is unique among the greater HDAC family due to its unusually narrow substrate specificity as a polyamine deacetylase, specifically as an -acetylspermidine hydrolase. Polyamines are essential for cell growth and proliferation; consequently, inhibition of polyamine deacetylation represents a possible strategy for cancer chemotherapy. In this work, we have designed six acetylated phenylthioketone inhibitors of HDAC10 containing positively charged - and -substituted amino groups designed to target interactions with E274, the gatekeeper that recognizes the positively charged ammonium group of the substrate -acetylspermidine. We prepared each of these inhibitors through a short synthetic route of six steps. By adapting a low-cost colorimetric activity assay, we measured low-micromolar IC values for these compounds against a humanized construct of zebrafish HDAC10 (A24E-D94A HDAC10). Selected inhibitors were cocrystallized with A24E-D94A zebrafish HDAC10 and zebrafish HDAC6 to provide insight into class IIb isozyme affinity and selectivity.

PubMed: 39411528
DOI: 10.1021/acsmedchemlett.4c00293

実験手法

X-RAY DIFFRACTION (1.46 Å)