A distal regulatory region of a class I human histone deacetylase
Open accessAbstract
Histone deacetylases (HDACs) are key enzymes in epigenetics and important drug targets in cancer biology. Whilst it has been established that HDACs regulate many cellular processes, far less is known about the regulation of these enzymes themselves. Here, we show that HDAC8 is allosterically regulated by shifts in populations between exchanging states. An inactive state is identified, which is stabilised by a range of mutations and resembles a sparsely-populated state in equilibrium with active HDAC8. Computational models show that the inactive and active states differ by small changes in a regulatory region that extends up to 28 Å from the active site. The regulatory allosteric region identified here in HDAC8 corresponds to regions in other class I HDACs known to bind regulators, thus suggesting a general mechanism. The presented results pave the way for the development of allosteric HDAC inhibitors and regulators to improve the therapy for several disease states.
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HDAC8 is subject to allosteric regulation, with populations moving back and forth between active and inactive states.
“HDAC8 is subject to allosteric regulation, with populations moving back and forth between active and inactive states.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Werbeck et al., 2020
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References 65 · Cited by 40
- Authors
- Werbeck, N. D., Shukla, V. K., Kunze, M. B. A., Yalinca, H., Pritchard, R. B., Siemons, L., Mondal, S., Greenwood, S. O. R., Kirkpatrick, J., Marson, C. M., & Hansen, D. F.
- Affiliations
- Institute of Structural and Molecular Biology (GB)
- University College London (GB)
- Corresponding author
- Hansen, D. Flemming
- ORCID
- Venue
- Nature Communications
- Published
- 2020-07-31
- Volume
- 11
- Issue
- 1
- Pages
- 3841-3841
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7395746
- OpenAlex
- W3046629476
- Cited by
- 40
- References
- 65
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 6 · 2023: 8 · 2022: 7 · 2021: 5 · 2020: 2
- FWCI
- 2.27
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Repository of Futwangen University of Applied Sciences (Furtwangen University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Funders
- Federation of European Biochemical Societies (WE 5563/1-1)
- Wellcome Trust (102404/13/Z/13, FC001029)
- RCUK | Engineering and Physical Sciences Research Council (EP/R029849/1)
- Cancer Research UK (FC001029)
- RCUK | MRC | Medical Research Foundation (FC001029)
- RCUK | Biotechnology and Biological Sciences Research Council (BB/H022570/1, BB/R000255/1)
- Leverhulme Trust (RPG-2016-268)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
- Keywords
- HDAC8, histone deacetylase, class I HDACs, allosteric regulation, distal regulatory regions, inactive state, enzyme activation, epigenetic regulation, allosteric inhibitors, protein conformational equilibrium, computational modeling
- MeSH terms
- Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Vorinostat, Allosteric Regulation, Allosteric Site, Cloning, Molecular, Enzyme Activation, Escherichia coli, Genetic Vectors, Histone Deacetylases, Humans, Hydroxamic Acids, Indoles, Mutation, Protein Binding, Recombinant Proteins, Repressor Proteins, Substrate Specificity, Thermodynamics, Gene Expression, Crystallography, X-Ray, Catalytic Domain, Protein Interaction Domains and Motifs, Molecular Dynamics Simulation, Histone Deacetylase Inhibitors
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