2V5W

Crystal structure of HDAC8-substrate complex

2V5W の概要

• エントリーDOI: 10.2210/pdb2v5w/pdb
• 関連するPDBエントリー: 2V5X
• 分子名称: HISTONE DEACETYLASE 8, GLYCYL-GLYCYL-GLYCINE, PEPTIDIC SUBSTRATE, ... (6 entities in total)
• 機能のキーワード: histone deacetylase, chromatin regulator, p53, hdac, hdac8, nucleus, repressor, hydrolase, nuclear protein, peptidic substrate, transcription regulation, chromatin, transcription, deacetylation, hydrolase-hydrolase substrate complex, hydrolase/hydrolase substrate
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 88468.22

構造登録者

Di Marco, S.,Vannini, A.,Volpari, C. (登録日: 2007-07-10, 公開日: 2007-09-04, 最終更新日: 2024-10-23)

主引用文献

Vannini, A.,Volpari, C.,Gallinari, P.,Jones, P.,Mattu, M.,Carfi, A.,Defrancesco, R.,Steinkuhler, C.,Di Marco, S.
Substrate Binding to Histone Deacetylases as Revealed by Crystal Structure of Hdac8-Substrate Complex
Embo Rep., 8:879-, 2007

PubMed Abstract: Histone deacetylases (HDACs)-an enzyme family that deacetylates histones and non-histone proteins-are implicated in human diseases such as cancer, and the first-generation of HDAC inhibitors are now in clinical trials. Here, we report the 2.0 A resolution crystal structure of a catalytically inactive HDAC8 active-site mutant, Tyr306Phe, bound to an acetylated peptidic substrate. The structure clarifies the role of active-site residues in the deacetylation reaction and substrate recognition. Notably, the structure shows the unexpected role of a conserved residue at the active-site rim, Asp 101, in positioning the substrate by directly interacting with the peptidic backbone and imposing a constrained cis-conformation. A similar interaction is observed in a new hydroxamate inhibitor-HDAC8 structure that we also solved. The crucial role of Asp 101 in substrate and inhibitor recognition was confirmed by activity and binding assays of wild-type HDAC8 and Asp101Ala, Tyr306Phe and Asp101Ala/Tyr306Phe mutants.

PubMed: 17721440
DOI: 10.1038/SJ.EMBOR.7401047

実験手法

X-RAY DIFFRACTION (2 Å)