6HU3

Crystal structure of Schistosoma mansoni HDAC8 complexed with a triazole hydroxamate inhibitor

6HU3 の概要

• エントリーDOI: 10.2210/pdb6hu3/pdb
• 分子名称: Histone deacetylase, ZINC ION, POTASSIUM ION, ... (7 entities in total)
• 機能のキーワード: epigenetics, histone deacetylase, hdac8, selective inhibitor, pathogen, hydrolase
• 由来する生物種: Schistosoma mansoni
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 206296.84

構造登録者

Shaik, T.B.,Marek, M.,Romier, C. (登録日: 2018-10-05, 公開日: 2018-10-31, 最終更新日: 2024-01-24)

主引用文献

Marek, M.,Shaik, T.B.,Heimburg, T.,Chakrabarti, A.,Lancelot, J.,Ramos-Morales, E.,Da Veiga, C.,Kalinin, D.,Melesina, J.,Robaa, D.,Schmidtkunz, K.,Suzuki, T.,Holl, R.,Ennifar, E.,Pierce, R.J.,Jung, M.,Sippl, W.,Romier, C.
Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants.
J. Med. Chem., 61:10000-10016, 2018

PubMed Abstract: Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet the currently FDA-approved HDAC inhibitors nonspecifically target at least several of the 11 structurally similar but functionally different HDAC isozymes, which hampers their broad usage in clinical settings. Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse. Here, we show that HDAC8-selective inhibitors adopt a L-shaped conformation required for their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1-L6 lock sterically prevents L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein engineering decreases potency of HDAC8-selective inhibitors and affects catalytic activity. Collectively, our results unravel key HDAC8 active site structural and functional determinants important for the design of next-generation chemical probes and epigenetic drugs.

PubMed: 30347148
DOI: 10.1021/acs.jmedchem.8b01087

実験手法

X-RAY DIFFRACTION (1.655 Å)