8D9C

Crystal Structure of Danio rerio histone deacetylase 6 catalytic domain 2 complexed with fluorinated inhibitor 10

8D9C の概要

• エントリーDOI: 10.2210/pdb8d9c/pdb
• 分子名称: Hdac6 protein, 2,3,4,5,6-pentafluoro-N-hydroxybenzamide, ZINC ION, ... (5 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: 81312.35

構造登録者

Watson, P.R.,Christianson, D.W. (登録日: 2022-06-09, 公開日: 2022-09-28, 最終更新日: 2023-10-18)

主引用文献

Watson, P.R.,Bai, P.,Wang, C.,Cragin, A.D.,Hooker, J.M.,Christianson, D.W.
Aromatic Ring Fluorination Patterns Modulate Inhibitory Potency of Fluorophenylhydroxamates Complexed with Histone Deacetylase 6.
Biochemistry, 61:1945-1954, 2022

PubMed Abstract: Bavarostat (EKZ-001) is a selective inhibitor of histone deacetylase 6 (HDAC6) that contains a -fluorophenylhydroxamate Zn-binding group. The recently determined crystal structure of its complex with HDAC6 from (zebrafish) revealed that the -fluoro substituent binds exclusively in an aromatic crevice defined by F583 and F643 rather than being oriented out toward solvent. To explore the binding of inhibitor C-F groups in this fluorophilic crevice, we now report a series of 10 simple fluorophenylhydroxamates bearing one or more fluorine atoms with different substitution patterns. Inhibitory potencies against human and zebrafish HDAC6 range widely from 121 to >30,000 nM. The best inhibitory potency is measured for -difluorophenylhydroxamate () with IC = 121 nM against human HDAC6; the worst inhibitory potencies are measured for -fluorophenylhydroxamate () as well as fluorophenylhydroxamates , , , and , although there are some variations in activity trends against human and zebrafish HDAC6. These studies show that aromatic ring fluorination at the meta position(s) does not improve inhibitory activity against human HDAC6 relative to the nonfluorinated parent compound phenylhydroxamate (IC = 120 nM), but meta-fluorination does not seriously compromise inhibitory activity either. Crystal structures of selected zebrafish HDAC6-fluorophenylhydroxamate complexes reveal that the fluoroaromatic ring is uniformly accommodated in the F583-F643 aromatic crevice, so ring fluorination does not perturb the inhibitor binding conformation. However, hydroxamate-Zn coordination is bidentate for some inhibitors and monodentate for others. These studies will inform design strategies underlying the design of F-labeled HDAC6 inhibitors intended for positron emission tomography.

PubMed: 36073962
DOI: 10.1021/acs.biochem.2c00332

実験手法

X-RAY DIFFRACTION (1.82 Å)