3RQD

Ideal Thiolate-Zinc Coordination Geometry in Depsipeptide Binding to Histone Deacetylase 8

3RQD の概要

• エントリーDOI: 10.2210/pdb3rqd/pdb
• 関連するBIRD辞書のPRD_ID: PRD_000785
• 分子名称: Histone deacetylase 8, Largazole, ZINC ION, ... (5 entities in total)
• 機能のキーワード: histone deacetylase, largazole, histone deacetylation, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Nucleus: Q9BY41
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 87852.62

構造登録者

Cole, K.E.,Dowling, D.P.,Christianson, D.W. (登録日: 2011-04-28, 公開日: 2011-08-24, 最終更新日: 2024-10-16)

主引用文献

Cole, K.E.,Dowling, D.P.,Boone, M.A.,Phillips, A.J.,Christianson, D.W.
Structural basis of the antiproliferative activity of largazole, a depsipeptide inhibitor of the histone deacetylases.
J.Am.Chem.Soc., 133:12474-12477, 2011

PubMed Abstract: Largazole is a macrocyclic depsipeptide originally isolated from the marine cyanobacterium Symploca sp., which is indigenous to the warm, blue-green waters of Key Largo, Florida (whence largazole derives its name). Largazole contains an unusual thiazoline-thiazole ring system that rigidifies its macrocyclic skeleton, and it also contains a lipophilic thioester side chain. Hydrolysis of the thioester in vivo yields largazole thiol, which exhibits remarkable antiproliferative effects and is believed to be the most potent inhibitor of the metal-dependent histone deacetylases (HDACs). Here, the 2.14 Å-resolution crystal structure of the HDAC8-largazole thiol complex is the first of an HDAC complexed with a macrocyclic inhibitor and reveals that ideal thiolate-zinc coordination geometry is the key chemical feature responsible for its exceptional affinity and biological activity. Notably, the core structure of largazole is conserved in romidepsin, a depsipeptide natural product formulated as the drug Istodax recently approved for cancer chemotherapy. Accordingly, the structure of the HDAC8-largazole thiol complex is the first to illustrate the mode of action of a new class of therapeutically important HDAC inhibitors.

PubMed: 21790156
DOI: 10.1021/ja205972n

実験手法

X-RAY DIFFRACTION (2.143 Å)