5FCW

HDAC8 Complexed with a Hydroxamic Acid

5FCW の概要

• エントリーDOI: 10.2210/pdb5fcw/pdb
• 分子名称: Histone deacetylase 8, 4-naphthalen-1-yl-~{N}-oxidanyl-benzamide, ZINC ION, ... (7 entities in total)
• 機能のキーワード: histone deacetylase, hdac8, hydroxamic acid, hydrolase
• 由来する生物種: Homo sapiens (Human)
• 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: 86899.30

構造登録者

Cole, K.E.,Perry, K. (登録日: 2015-12-15, 公開日: 2016-10-26, 最終更新日: 2024-03-06)

主引用文献

Tabackman, A.A.,Frankson, R.,Marsan, E.S.,Perry, K.,Cole, K.E.
Structure of 'linkerless' hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket.
J.Struct.Biol., 195:373-378, 2016

PubMed Abstract: Histone deacetylases (HDACs) catalyze the hydrolysis of acetylated lysine side chains in histone and non-histone proteins, and play a critical role in the regulation of many biological processes, including cell differentiation, proliferation, senescence, and apoptosis. Aberrant HDAC activity is associated with cancer, making these enzymes important targets for drug design. In general, HDAC inhibitors (HDACi) block the proliferation of tumor cells by inducing cell differentiation, cell cycle arrest, and/or apoptosis, and comprise some of the leading therapies in cancer treatments. To date, four HDACi have been FDA approved for the treatment of cancers: suberoylanilide hydroxamic acid (SAHA, Vorinostat, Zolinza®), romidepsin (FK228, Istodax®), belinostat (Beleodaq®), and panobinostat (Farydak®). Most current inhibitors are pan-HDACi, and non-selectively target a number of HDAC isoforms. Six previously reported HDACi were rationally designed, however, to target a unique sub-pocket found only in HDAC8. While these inhibitors were indeed potent against HDAC8, and even demonstrated specificity for HDAC8 over HDACs 1 and 6, there were no structural data to confirm the mode of binding. Here we report the X-ray crystal structure of Compound 6 complexed with HDAC8 to 1.98Å resolution. We also describe the use of molecular docking studies to explore the binding interactions of the other 5 related HDACi. Our studies confirm that the HDACi induce the formation of and bind in the HDAC8-specific subpocket, offering insights into isoform-specific inhibition.

PubMed: 27374062
DOI: 10.1016/j.jsb.2016.06.023

実験手法

X-RAY DIFFRACTION (1.979 Å)