Unusual zinc-binding mode of HDAC6-selective hydroxamate inhibitors
Open accessAbstract
Significance: Histone deacetylase 6 (HDAC6) is a zinc metalloenzyme that serves as the tubulin deacetylase in the cell cytosol. Inhibition of tubulin deacetylase activity leads to suppression of microtubule dynamics, causing cell cycle arrest and apoptosis, which is a validated strategy for cancer chemotherapy. Selective inhibition of HDAC6 is clinically preferable, since unwanted inhibition of other HDAC isozymes can lead to undesirable off-target effects. Here, X-ray crystal structures of HDAC6-inhibitor complexes reveal molecular features responsible for the isozyme selectivity measured in inhibition assays, including an unusual monodentate hydroxamate-Zn 2+ coordination mode as well as intermolecular interactions of bulky inhibitor substituents. These observations will inform the design of HDAC6-selective inhibitors with improved properties.
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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 [43]
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 [43]
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- Authors
- Porter, N. J., Mahendran, A., Breslow, R., & Christianson, D. W.
- Affiliations
- University of Pennsylvania (US)
- Columbia University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-12-04
- Volume
- 114
- Issue
- 51
- Pages
- 13459-13464
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5754815
- OpenAlex
- W2773548225
- Cited by
- 190
- References
- 12
- Citations by year
- 2026: 14 · 2025: 33 · 2024: 18 · 2023: 14 · 2022: 17 · 2021: 27 · 2020: 31 · 2019: 20 · 2018: 16
- FWCI
- 8.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- U.S. Department of Energy (DE‐ AC02‐06CH11357, -AC02-05CH11231, 76SF00515, AC02‐06CH11357, DE–AC02–76SF00515, 05CH11231, P41 GM103403, P41GM103393, DE AC02 05CH11231, AC02‐76SF00515, 06CH11357, DE-AC02-)
- Celgene
- National Institutes of Health (DE-AC02–05CH11231, DE-AC02–06CH11357, DE-AC02-76SF00515, GM103403)
- Office of Science (AC02-76SF00515, P41GM103393, AC02‐06CH11357, DEAC02–05CH11231, AC02-05CH11231, DE-AC02-76SF0051 5, DE-AC02, 06CH11357, 76SF00515, DE-AC02-06CH11357)
- National Institute of General Medical Sciences (DE-AC02-05CH11231, GM49758, DE-AC02-06CH11357, DE-AC02-76SF00515, GM071339, GM-103403, P41GM103393, P41GM103403, T32GM071339, R01GM049758)
- National Center for Research Resources (S10RR029205)
- Basic Energy Sciences (DE-AC02, DE-AC02-05CH11231., P41GM103393, DE-AC- 02-06CH11357, AC02‐06CH11357, AC02–05CH11231, 76SF00515, AC02-76SF00515, GM103403, 06CH11357, DE-AC-02-76SF00515)
- Biological and Environmental Research (05CH11231, P41 GM103393, DE-AC02 − 05CH11231, DEAC0206CH11357, DE- AC0276SF00515, AC02-05CH11231)
- Argonne National Laboratory (DE- AC02-06-CH11357, DE-AC02, AC02–06CH11357, P41 GM103403, DE-AC02-05CH11231, 06CH11357, S10 RR029205, DE-AC02-76SF00515)
- SLAC National Accelerator Laboratory (DE-AC02-05-CH11231, DEAC02−76SF00515, AC02‐76SF00515, DE-AC02-06CH11357, P41GM103393)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- HDAC6, hydroxamate inhibitors, monodentate coordination, isozyme selectivity, microtubule dynamics, cancer chemotherapy, inhibitor design, X-ray crystal structure
- MeSH terms
- Histone Deacetylase 6, Animals, Binding Sites, Hydroxamic Acids, Protein Binding, Zebrafish, Zinc, Zebrafish Proteins, Histone Deacetylase Inhibitors, Molecular Docking Simulation
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