Unusual zinc-binding mode of HDAC6-selective hydroxamate inhibitors

Porter, Nicholas J.; Mahendran, Adaickapillai; Breslow, Ronald; Christianson, David W.

doi:10.1073/pnas.1718823114

Unusual zinc-binding mode of HDAC6-selective hydroxamate inhibitors

Journal Article · Mon Dec 04 00:00:00 EST 2017 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1718823114· OSTI ID:1426287

Porter, Nicholas J. ^[1]; Mahendran, Adaickapillai ^[2]; Breslow, Ronald ^[2]; Christianson, David W. ^[1]

Univ. of Pennsylvania, Philadelphia, PA (United States)
Columbia Univ., New York, NY (United States)

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. As a result, structural comparisons of HDAC6-inhibitor complexes with class I HDACs suggest active site features that contribute to the isozyme selectivity observed in biochemical assays.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: NIH; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22). Scientific User Facilities Division; USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)

Grant/Contract Number:: AC02-05CH11231; AC02-06CH11357; AC02-76SF00515

OSTI ID:: 1426287

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 51 Vol. 114; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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