4LY1

Structure of Human HDAC2 in complex with inhibitor 4-(acetylamino)-N-[2-amino-5-(thiophen-2-yl)phenyl]benzamide

4LY1 の概要

• エントリーDOI: 10.2210/pdb4ly1/pdb
• 関連するPDBエントリー: 4LXZ
• 分子名称: Histone deacetylase 2, ZINC ION, CALCIUM ION, ... (8 entities in total)
• 機能のキーワード: deacetylase, histone, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus: Q92769
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 130302.50

構造登録者

Fong, R.,Lupardus, P.J. (登録日: 2013-07-30, 公開日: 2013-08-21, 最終更新日: 2023-09-20)

主引用文献

Lauffer, B.E.,Mintzer, R.,Fong, R.,Mukund, S.,Tam, C.,Zilberleyb, I.,Flicke, B.,Ritscher, A.,Fedorowicz, G.,Vallero, R.,Ortwine, D.F.,Gunzner, J.,Modrusan, Z.,Neumann, L.,Koth, C.M.,Lupardus, P.J.,Kaminker, J.S.,Heise, C.E.,Steiner, P.
Histone Deacetylase (HDAC) Inhibitor Kinetic Rate Constants Correlate with Cellular Histone Acetylation but Not Transcription and Cell Viability.
J.Biol.Chem., 288:26926-26943, 2013

PubMed Abstract: Histone deacetylases (HDACs) are critical in the control of gene expression, and dysregulation of their activity has been implicated in a broad range of diseases, including cancer, cardiovascular, and neurological diseases. HDAC inhibitors (HDACi) employing different zinc chelating functionalities such as hydroxamic acids and benzamides have shown promising results in cancer therapy. Although it has also been suggested that HDACi with increased isozyme selectivity and potency may broaden their clinical utility and minimize side effects, the translation of this idea to the clinic remains to be investigated. Moreover, a detailed understanding of how HDACi with different pharmacological properties affect biological functions in vitro and in vivo is still missing. Here, we show that a panel of benzamide-containing HDACi are slow tight-binding inhibitors with long residence times unlike the hydroxamate-containing HDACi vorinostat and trichostatin-A. Characterization of changes in H2BK5 and H4K14 acetylation following HDACi treatment in the neuroblastoma cell line SH-SY5Y revealed that the timing and magnitude of histone acetylation mirrored both the association and dissociation kinetic rates of the inhibitors. In contrast, cell viability and microarray gene expression analysis indicated that cell death induction and changes in transcriptional regulation do not correlate with the dissociation kinetic rates of the HDACi. Therefore, our study suggests that determining how the selective and kinetic inhibition properties of HDACi affect cell function will help to evaluate their therapeutic utility.

PubMed: 23897821
DOI: 10.1074/jbc.M113.490706

実験手法

X-RAY DIFFRACTION (1.57 Å)