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

doi:10.1038/nchembio.2140

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

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 +2 more·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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Selective inhibition appears to rely on small structural differences between HDAC1-3 and HDAC6 and on small thermodynamic differences in selective inhibitor binding.
“Selective inhibition appears to rely on small structural differences between HDAC1-3 and HDAC6 and on small thermodynamic differences in selective inhibitor binding 42-46 .”
From Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants (2018) · cites this paper as [44]
Recent work on HDAC6/inhibitor complexes demonstrates that L1 loop conformational stability is important for interactions of L1 loop residues with inhibitor capping groups to achieve HDAC6 selectivity inhibition.
“the recent work on HDAC6/inhibitor complexes demonstrate that L1 loop conformational stability is important for the interactions of L1 loop residues with inhibitors capping groups to achieve HDAC6 selectivity inhibition 42-46”
From Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants (2018) · cites this paper as [44]
HDAC10 PDAC-ΨDAC heterodomain assembly resembles HDAC6 heterodomain assembly and HDAC homodomain assembly in Schizosaccharomyces pombe Clr3.
“HDAC10 PDAC-ΨDAC heterodomain assembly resembles HDAC6 heterodomain assembly and HDAC homodomain assembly in Schizosaccharomyces pombe Clr3 (Supplementary Fig. 5)2728.”
From Histone deacetylase 10 structure and molecular function as a polyamine deacetylase (2017) · cites this paper as [27]

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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
Physical Sciences › Materials Science › Materials Chemistry › 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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