HDAC8型
化学
表观遗传学
同工酶
活动站点
组蛋白脱乙酰基酶
组蛋白
药物发现
生物化学
计算生物学
酶
生物
DNA
基因
作者
Martin Marek,T.B. Shaik,Tino Heimburg,Alokta Chakrabarti,Julien Lancelot,Elizabeth Ramos‐Morales,Cyrielle Da Veiga,Dmitrii V. Kalinin,Jelena Melesina,Dina Robaa,Karin Schmidtkunz,Takayoshi Suzuki,Ralph Holl,Eric Ennifar,Raymond J. Pierce,Manfred Jung,Wolfgang Sippl,Christophe Romier
标识
DOI:10.1021/acs.jmedchem.8b01087
摘要
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.
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