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Cited by 153Histone Deacetylase Inhibitors ResearchEnzyme Structure and FunctionEnzyme function and inhibition

Structural Basis of the Antiproliferative Activity of Largazole, a Depsipeptide Inhibitor of the Histone Deacetylases

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Cole, Kathryn E., Dowling, Daniel P., Boone, Matthew A., Phillips, Andrew J., Christianson, David W.·2011·Journal of the American Chemical Society
DOI 10.1021/ja205972nPMC PMC3162211
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Abstract

Largazole is a macrocyclic depsipeptide originally isolated from the marine cyanobacterium Symploca sp., which is indigenous to the warm, blue-green waters of Key Largo, Florida (whence largazole derives its name). Largazole contains an unusual thiazoline-thiazole ring system that rigidifies its macrocyclic skeleton, and it also contains a lipophilic thioester side chain. Hydrolysis of the thioester in vivo yields largazole thiol, which exhibits remarkable antiproliferative effects and is believed to be the most potent inhibitor of the metal-dependent histone deacetylases (HDACs). Here, the 2.14 Å-resolution crystal structure of the HDAC8-largazole thiol complex is the first of an HDAC complexed with a macrocyclic inhibitor and reveals that ideal thiolate-zinc coordination geometry is the key chemical feature responsible for its exceptional affinity and biological activity. Notably, the core structure of largazole is conserved in romidepsin, a depsipeptide natural product formulated as the drug Istodax recently approved for cancer chemotherapy. Accordingly, the structure of the HDAC8-largazole thiol complex is the first to illustrate the mode of action of a new class of therapeutically important HDAC inhibitors.

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  • In HDAC8, the L1 and L2 loops have been shown to display flexibility, being able to change their conformation to adapt to different inhibitors such as the large Largazole inhibitor and its analogues.

    “In HDAC8, the L1 and L2 loops have been shown to display flexibility, being able to change their conformation to adapt to different inhibitors such as the large Largazole inhibitor and its analogues (Figure S7) 40, 41”

    From Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants (2018) · cites this paper as [40]

    The discussion of Fig. 3b describes L1 and L2 loop shifts that accommodate bulky largazole thiol and compares some shifts with those seen for another inhibitor, M344. It discusses largazole analogues, but only suggests that one analogue likely triggers a similar change; it does not show L1 and L2 adapting to largazole analogues. (LLM, conf=0.86)

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Authors
Cole, K. E., Dowling, D. P., Boone, M. A., Phillips, A. J., & Christianson, D. W.
Affiliations
  • University of Pennsylvania (US)
  • Yale University (US)
Corresponding author
Christianson, David W.
ORCID
Venue
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Published
2011-07-26
Volume
133
Issue
32
Pages
12474-12477
ISSN
  • 0002-7863 (ISSN-L)
  • 1520-5126
DOI
10.1021/ja205972n
PMC
PMC3162211
OpenAlex
W2122863655
Cited by
153
References
3
Citations by year
2026: 6 · 2025: 6 · 2024: 3 · 2023: 6 · 2022: 3 · 2021: 14 · 2020: 13 · 2019: 14 · 2018: 8 · 2017: 11 · 2016: 10 · 2015: 18 · 2014: 21 · 2013: 5 · 2012: 12
FWCI
5.59
Type
journal article
Language
en
Open access
Locations
  • Journal of the American Chemical Society (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (CA110246, R56CA110246, R01CA110246)
  • National Institute of General Medical Sciences (GM49758, R01GM049758)
  • National Institute of Biomedical Imaging and Bioengineering (P30EB009998)
  • National Center for Research Resources (P41RR012408)
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, depsipeptides, crystal structure, antiproliferative activity, romidepsin, Symploca, marine cyanobacteria, thioester hydrolysis
MeSH terms
Cyanobacteria, Histone Deacetylases, Humans, Models, Molecular, Repressor Proteins, Thiazoles, Crystallography, X-Ray, Depsipeptides, Histone Deacetylase Inhibitors

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