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Cited by 58Histone Deacetylase Inhibitors ResearchEnzyme Structure and FunctionEnzyme function and inhibition

Variable Active Site Loop Conformations Accommodate the Binding of Macrocyclic Largazole Analogues to HDAC8

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Decroos, Christophe, Clausen, Dane J., Haines, Brandon E., Wiest, Olaf, Williams, Robert M., Christianson, David W.·2015·Biochemistry
DOI 10.1021/acs.biochem.5b00010PMC PMC4382410
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Abstract

The macrocyclic depsipeptide Largazole is a potent inhibitor of metal-dependent histone deacetylases (HDACs), some of which are drug targets for cancer chemotherapy. Indeed, Largazole partially resembles Romidepsin (FK228), a macrocyclic depsipeptide already approved for clinical use. Each inhibitor contains a pendant side chain thiol that coordinates to the active site Zn(2+) ion, as observed in the X-ray crystal structure of the HDAC8-Largazole complex [Cole, K. E., Dowling, D. P., Boone, M. A., Phillips, A. J., and Christianson, D. W. (2011) J. Am. Chem. Soc. 133, 12474]. Here, we report the X-ray crystal structures of HDAC8 complexed with three synthetic analogues of Largazole in which the depsipeptide ester is replaced with a rigid amide linkage. In two of these analogues, a six-membered pyridine ring is also substituted (with two different orientations) for the five-membered thiazole ring in the macrocycle skeleton. The side chain thiol group of each analogue coordinates to the active site Zn(2+) ion with nearly ideal geometry, thereby preserving the hallmark structural feature of inhibition by Largazole. Surprisingly, in comparison with the binding of Largazole, these analogues trigger alternative conformational changes in loops L1 and L2 flanking the active site. However, despite these structural differences, inhibitory potency is generally comparable to, or just moderately less than, the inhibitory potency of Largazole. Thus, this study reveals important new structure-affinity relationships for the binding of macrocyclic inhibitors to HDAC8.

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Cited by

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Authors
Decroos, C., Clausen, D. J., Haines, B. E., Wiest, O., Williams, R. M., & Christianson, D. W.
Affiliations
  • University of Pennsylvania (US)
  • Colorado State University (US)
  • University of Notre Dame (US)
  • University of Colorado Cancer Center (US)
Corresponding author
Christianson, David W.
ORCID
Venue
Biochemistry
Publisher
American Chemical Society (ACS)
Published
2015-03-20
Volume
54
Issue
12
Pages
2126-2135
ISSN
  • 0006-2960 (ISSN-L)
  • 1520-4995
DOI
10.1021/acs.biochem.5b00010
PMC
PMC4382410
OpenAlex
W2069312697
Cited by
58
References
6
Citations by year
2026: 1 · 2025: 1 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 8 · 2019: 8 · 2018: 6 · 2017: 11 · 2016: 7 · 2015: 5
FWCI
4.63
Type
journal article
Language
en
Open access
Locations
  • Biochemistry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of General Medical Sciences (GM49758)
  • National Cancer Institute (CA152314)
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
largazole, HDAC8, histone deacetylase inhibitors, romidepsin, zinc coordination, loop conformational change, structure-affinity relationships, amide linkage, protein-ligand binding
MeSH terms
Histone Deacetylases, Humans, Models, Molecular, Protein Conformation, Recombinant Proteins, Repressor Proteins, Thiazoles, Mutagenesis, Site-Directed, Crystallography, X-Ray, Catalytic Domain, Depsipeptides, Molecular Dynamics Simulation, Histone Deacetylase Inhibitors

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