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标题：Unusual zinc-binding mode of HDAC6-selective hydroxamate inhibitors
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作者：Nicholas J. Porter ; Adaickapillai Mahendran ; Ronald Breslow 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：51
页码：13459-13464
DOI：10.1073/pnas.1718823114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Histone deacetylases (HDACs) regulate myriad cellular processes by catalyzing the hydrolysis of acetyl– l -lysine residues in histone and nonhistone proteins. The Zn²⁺-dependent class IIb enzyme HDAC6 regulates microtubule function by deacetylating α-tubulin, which suppresses microtubule dynamics and leads to cell cycle arrest and apoptosis. Accordingly, HDAC6 is a target for the development of selective inhibitors that might be useful in new therapeutic approaches for the treatment of cancer, neurodegenerative diseases, and other disorders. Here, we present high-resolution structures of catalytic domain 2 from Danio rerio HDAC6 (henceforth simply “HDAC6”) complexed with compounds that selectively inhibit HDAC6 while maintaining nanomolar inhibitory potency: N -hydroxy-4-[( N (2-hydroxyethyl)-2-phenylacetamido)methyl)-benzamide)] (HPB), ACY-1215 (Ricolinostat), and ACY-1083. These structures reveal that an unusual monodentate Zn²⁺ coordination mode is exploited by sterically bulky HDAC6-selective phenylhydroxamate inhibitors. We additionally report the ultrahigh-resolution structure of the HDAC6–trichostatin A complex, which reveals two Zn²⁺-binding conformers for the inhibitor: a major conformer (70%) with canonical bidentate hydroxamate-Zn²⁺ coordination geometry and a minor conformer (30%) with monodentate hydroxamate-Zn²⁺ coordination geometry, reflecting a free energy difference of only 0.5 kcal/mol. The minor conformer is not visible in lower resolution structure determinations. Structural comparisons of HDAC6-inhibitor complexes with class I HDACs suggest active site features that contribute to the isozyme selectivity observed in biochemical assays.
关键词：protein crystallography ; metalloenzyme ; enzyme inhibitor ; drug discovery ; cancer chemotherapy