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Histone Deacetylase 6-Selective Inhibitors and the Influence of Capping Groups on Hydroxamate-Zinc Denticity
Open accessAbstract
Four crystal structures are presented of histone deacetylase 6 (HDAC6) complexes with para -substituted phenylhydromaxamate inhibitors, including bulky peptoids. These structures provide insight regarding the design of capping groups that confer selectivity for binding to HDAC6, specifically with regard to interactions in a pocket formed by the L1 loop. Capping group interactions may also influence hydroxamate-Zn 2+ coordination with monodentate or bidentate geometry.
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“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 [45]
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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 [45]
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Metadata
- Authors
- Porter, N. J., Osko, J. D., Diedrich, D., Kurz, T., Hooker, J. M., Hansen, F. K., & Christianson, D. W.
- Affiliations
- University of Pennsylvania (US)
- Heinrich Heine University Düsseldorf (DE)
- Harvard University (US)
- Corresponding author
- Christianson, David W.
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-08-17
- Volume
- 61
- Issue
- 17
- Pages
- 8054-8060
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC6136958
- OpenAlex
- W2887296525
- Cited by
- 111
- References
- 43
- Citations by year
- 2026: 11 · 2025: 16 · 2024: 8 · 2023: 8 · 2022: 10 · 2021: 16 · 2020: 21 · 2019: 15 · 2018: 6
- FWCI
- 6.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (HA 7783/1-1)
- National Institute of General Medical Sciences (GM49758)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Keywords
- HDAC6, HDAC6 inhibitors, capping groups, peptoids, L1 loop, enzyme selectivity, crystal structure
- MeSH terms
- Histone Deacetylase 6, Animals, Hydroxamic Acids, Protein Conformation, Zebrafish, Zinc, Molecular Structure, Crystallography, X-Ray, Zebrafish Proteins, Histone Deacetylase Inhibitors, Coordination Complexes
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