5W5K

Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 in complex with KV70

5W5K の概要

• エントリーDOI: 10.2210/pdb5w5k/pdb
• 分子名称: Histone deacetylase 6, ZINC ION, POTASSIUM ION, ... (5 entities in total)
• 機能のキーワード: histone deacetylase, hydrolase, tubulin deacetylase
• 由来する生物種: Danio rerio (Zebrafish)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 122338.51

構造登録者

Porter, N.J.,Christianson, D.W. (登録日: 2017-06-15, 公開日: 2018-06-27, 最終更新日: 2023-10-04)

主引用文献

Vogerl, K.,Ong, N.,Senger, J.,Herp, D.,Schmidtkunz, K.,Marek, M.,Muller, M.,Bartel, K.,Shaik, T.B.,Porter, N.J.,Robaa, D.,Christianson, D.W.,Romier, C.,Sippl, W.,Jung, M.,Bracher, F.
Synthesis and Biological Investigation of Phenothiazine-Based Benzhydroxamic Acids as Selective Histone Deacetylase 6 Inhibitors.
J.Med.Chem., 62:1138-1166, 2019

PubMed Abstract: The phenothiazine system was identified as a favorable cap group for potent and selective histone deacetylase 6 (HDAC6) inhibitors. Here, we report the preparation and systematic variation of phenothiazines and their analogues containing a benzhydroxamic acid moiety as the zinc-binding group. We evaluated their ability to selectively inhibit HDAC6 by a recombinant HDAC enzyme assay, by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines. Structure-activity relationship studies revealed that incorporation of a nitrogen atom into the phenothiazine framework results in increased potency and selectivity for HDAC6 (more than 500-fold selectivity relative to the inhibition of HDAC1, HDAC4, and HDAC8), as rationalized by molecular modeling and docking studies. The binding mode was confirmed by co-crystallization of the potent azaphenothiazine inhibitor with catalytic domain 2 from Danio rerio HDAC6.

PubMed: 30645113
DOI: 10.1021/acs.jmedchem.8b01090

実験手法

X-RAY DIFFRACTION (2.7 Å)