Cited by 355Histone Deacetylase Inhibitors ResearchEnzyme Structure and FunctionEnzyme function and inhibition

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Structural insights into HDAC6 tubulin deacetylation and its selective inhibition

Miyake, Yasuyuki, Keusch, Jeremy J, Wang, Longlong, Saito, Makoto, Hess, Daniel, Wang, Xiaoning, Melancon, Bruce J, Helquist, Paul, Gut, Heinz, Matthias, Patrick·2016·Nature Chemical Biology

DOI 10.1038/nchembio.2140

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Abstract

We report crystal structures of zebrafish histone deacetylase 6 (HDAC6) catalytic domains in tandem or as single domains in complex with the (R) and (S) enantiomers of trichostatin A (TSA) or with the HDAC6-specific inhibitor nexturastat A. The tandem domains formed, together with the inter-domain linker, an ellipsoid-shaped complex with pseudo-twofold symmetry. We identified important active site differences between both catalytic domains and revealed the binding mode of HDAC6 selective inhibitors. HDAC inhibition assays with (R)- and (S)-TSA showed that (R)-TSA was a broad-range inhibitor, whereas (S)-TSA had moderate selectivity for HDAC6. We identified a uniquely positioned α-helix and a flexible tryptophan residue in the loop joining α-helices H20 to H21 as critical for deacetylation of the physiologic substrate tubulin. Using single-molecule measurements and biochemical assays we demonstrated that HDAC6 catalytic domain 2 deacetylated α-tubulin lysine 40 in the lumen of microtubules, but that its preferred substrate was unpolymerized tubulin.

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Authors: Miyake, Y., Keusch, J. J., Wang, L., Saito, M., Hess, D., Wang, X., Melancon, B. J., Helquist, P., Gut, H., & Matthias, P.
Affiliations: Friedrich Miescher Institute (CH)
University of Notre Dame (US)
University of Basel (CH)
Corresponding author: Matthias, Patrick
ORCID: Miyake, Yasuyuki
Keusch, Jeremy J
Wang, Longlong
Saito, Makoto
Hess, Daniel
Melancon, Bruce J
Helquist, Paul
Gut, Heinz
Matthias, Patrick
Venue: Nature Chemical Biology
Publisher: Springer Science and Business Media LLC
Published: 2016-07-25
Volume: 12
Issue: 9
Pages: 748-754
ISSN: 1552-4450 (ISSN-L)
1552-4469
DOI: 10.1038/nchembio.2140
OpenAlex: W2482664294
Cited by: 315
References: 58
Citations by year: 2026: 31 · 2025: 32 · 2024: 24 · 2023: 31 · 2022: 27 · 2021: 39 · 2020: 36 · 2019: 37 · 2018: 34 · 2017: 18 · 2016: 6
FWCI: 17.15
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Chemical Biology (publishedVersion)
PubMed (publishedVersion)
DORA PSI (Paul Scherrer Institute) (submittedVersion)
Funders: National Institute of Neurological Disorders and Stroke (R01NS092653)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
Keywords: HDAC6, histone deacetylase, tubulin deacetylation, trichostatin A, crystal structure, enantiomers, enzyme inhibition, microtubules, active site, zebrafish
MeSH terms: Histone Deacetylase 6, Acetylation, Animals, Histone Deacetylases, Humans, Hydroxamic Acids, Models, Molecular, Structure-Activity Relationship, Tubulin, Zebrafish, Zebrafish Proteins, Biocatalysis, Histone Deacetylase Inhibitors

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Structural insights into HDAC6 tubulin deacetylation and its selective inhibition

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