8EQI

Crystal Structure of Danio rerio histone deacetylase 6 catalytic domain 2 complexed with cyclopeptide des4.2.0

8EQI の概要

• エントリーDOI: 10.2210/pdb8eqi/pdb
• 分子名称: Hdac6 protein, Cyclopeptide des4.2.0, 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); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 82888.42

構造登録者

Watson, P.R.,Christianson, D.W. (登録日: 2022-10-07, 公開日: 2023-04-19, 最終更新日: 2024-10-16)

主引用文献

Watson, P.R.,Gupta, S.,Hosseinzadeh, P.,Brown, B.P.,Baker, D.,Christianson, D.W.
Macrocyclic Octapeptide Binding and Inferences on Protein Substrate Binding to Histone Deacetylase 6.
Acs Chem.Biol., 18:959-968, 2023

PubMed Abstract: Histone deacetylases (HDACs) are essential for the regulation of myriad biological processes, and their aberrant function is implicated in cancer, neurodegeneration, and other diseases. The cytosolic isozyme HDAC6 is unique among the greater family of deacetylases in that it contains two catalytic domains, CD1 and CD2. HDAC6 CD2 is responsible for tubulin deacetylase and tau deacetylase activities, inhibition of which is a key goal as new therapeutic approaches are explored. Of particular interest as HDAC inhibitors are naturally occurring cyclic tetrapeptides such as Trapoxin A or HC Toxin, or the cyclic depsipeptides Largazole and Romidepsin. Even more intriguing are larger, computationally designed macrocyclic peptide inhibitors. Here, we report the 2.0 Å resolution crystal structure of HDAC6 CD2 complexed with macrocyclic octapeptide . Comparison with the previously reported structure of the complex with macrocyclic octapeptide reveals that a potent thiolate-zinc interaction made by the unnatural amino acid ()-2-amino-7-sulfanylheptanoic acid contributes to nanomolar inhibitory potency for each inhibitor. Apart from this zinc-binding residue, octapeptides adopt strikingly different overall conformations and make few direct hydrogen bonds with the protein. Intermolecular interactions are dominated by water-mediated hydrogen bonds; in essence, water molecules appear to cushion the enzyme-octapeptide interface. In view of the broad specificity observed for protein substrates of HDAC6 CD2, we suggest that the binding of macrocyclic octapeptides may mimic certain features of the binding of macromolecular protein substrates.

PubMed: 37027789
DOI: 10.1021/acschembio.3c00113

実験手法

X-RAY DIFFRACTION (2 Å)