1W22

Crystal structure of inhibited human HDAC8

1W22 の概要

• エントリーDOI: 10.2210/pdb1w22/pdb
• 関連するPDBエントリー: 1T64 1T67 1T69 1VKG
• 分子名称: HISTONE DEACETYLASE 8, ZINC ION, POTASSIUM ION, ... (5 entities in total)
• 機能のキーワード: hydroxamic acid, chromatin, deacetylation, hdac, hydrolase, nuclear protein, repressor
• 由来する生物種: HOMO SAPIENS
• 細胞内の位置: Nucleus: Q9BY41
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 84671.06

構造登録者

Vannini, A.,Volpari, C.,Caroli Casavola, E.,Di Marco, S. (登録日: 2004-06-25, 公開日: 2004-09-24, 最終更新日: 2023-12-13)

主引用文献

Vannini, A.,Volpari, C.,Filocamo, G.,Caroli Casavola, E.,Brunetti, M.,Renzoni, D.,Chakravarty, P.,Paolini, C.,De Francesco, R.,Gallinari, P.,Steinckuhler, C.,Di Marco, S.
Crystal Structure of a Eukaryotic Zn-Dependent Histone Deacetylase,Human Hdac8,Complexed with a Hydroxamic Acid Inhibitor
Proc.Natl.Acad.Sci.USA, 101:15064-, 2004

PubMed Abstract: Histone deacetylases (HDACs) are a family of enzymes involved in the regulation of gene expression, DNA repair, and stress response. These processes often are altered in tumors, and HDAC inhibitors have had pronounced antitumor activity with promising results in clinical trials. Here, we report the crystal structure of human HDAC8 in complex with a hydroxamic acid inhibitor. Such a structure of a eukaryotic zinc-dependent HDAC has not be described previously. Similar to bacterial HDAC-like protein, HDAC8 folds in a single alpha/beta domain. The inhibitor and the zinc-binding sites are similar in both proteins. However, significant differences are observed in the length and structure of the loops surrounding the active site, including the presence of two potassium ions in HDAC8 structure, one of which interacts with key catalytic residues. CD data suggest a direct role of potassium in the fold stabilization of HDAC8. Knockdown of HDAC8 by RNA interference inhibits growth of human lung, colon, and cervical cancer cell lines, highlighting the importance of this HDAC subtype for tumor cell proliferation. Our findings open the way for the design and development of selective inhibitors of HDAC8 as possible antitumor agents.

PubMed: 15477595
DOI: 10.1073/PNAS.0404603101

実験手法

X-RAY DIFFRACTION (2.5 Å)