2VQW

Structure of inhibitor-free HDAC4 catalytic domain (with gain-of- function mutation His332Tyr)

2VQW の概要

• エントリーDOI: 10.2210/pdb2vqw/pdb
• 関連するPDBエントリー: 2VQJ 2VQM 2VQO 2VQQ 2VQV
• 分子名称: HISTONE DEACETYLASE 4, POTASSIUM ION, ZINC ION (3 entities in total)
• 機能のキーワード: inhibitor, repressor, chromatin, coiled coil, histone deacetylase, transcription regulation, ubl conjugation, chromatin regulator, polymorphism, transcription, phosphoprotein, hdac, zinc, hdaci, nucleus, hydrolase, cytoplasm
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Nucleus: P56524
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 44711.44

構造登録者

Bottomley, M.J.,Lo Surdo, P.,Di Giovine, P.,Cirillo, A.,Scarpelli, R.,Ferrigno, F.,Jones, P.,Neddermann, P.,De Francesco, R.,Steinkuhler, C.,Gallinari, P.,Carfi, A. (登録日: 2008-03-19, 公開日: 2008-08-05, 最終更新日: 2023-12-13)

主引用文献

Bottomley, M.J.,Lo Surdo, P.,Di Giovine, P.,Cirillo, A.,Scarpelli, R.,Ferrigno, F.,Jones, P.,Neddermann, P.,De Francesco, R.,Steinkuhler, C.,Gallinari, P.,Carfi, A.
Structural and Functional Analysis of the Human Hdac4 Catalytic Domain Reveals a Regulatory Structural Zinc-Binding Domain.
J.Biol.Chem., 283:26694-, 2008

PubMed Abstract: Histone deacetylases (HDACs) regulate chromatin status and gene expression, and their inhibition is of significant therapeutic interest. To date, no biological substrate for class IIa HDACs has been identified, and only low activity on acetylated lysines has been demonstrated. Here, we describe inhibitor-bound and inhibitor-free structures of the histone deacetylase-4 catalytic domain (HDAC4cd) and of an HDAC4cd active site mutant with enhanced enzymatic activity toward acetylated lysines. The structures presented, coupled with activity data, provide the molecular basis for the intrinsically low enzymatic activity of class IIa HDACs toward acetylated lysines and reveal active site features that may guide the design of class-specific inhibitors. In addition, these structures reveal a conformationally flexible structural zinc-binding domain conserved in all class IIa enzymes. Importantly, either the mutation of residues coordinating the structural zinc ion or the binding of a class IIa selective inhibitor prevented the association of HDAC4 with the N-CoR.HDAC3 repressor complex. Together, these data suggest a key role of the structural zinc-binding domain in the regulation of class IIa HDAC functions.

PubMed: 18614528
DOI: 10.1074/JBC.M803514200

実験手法

X-RAY DIFFRACTION (3 Å)