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Structural insights into HDAC6 tubulin deacetylation and its selective inhibition
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 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]
In the citing paper
“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]
In the citing paper
“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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Metadata
- 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
- Venue
- Nature Chemical Biology
- Published
- 2016-07-25
- Volume
- 12
- Issue
- 9
- Pages
- 748-754
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- 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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