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Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid

Alessandro Vannini1, Cinzia Volpari, Gessica Filocamo

  • 1Department of Biochemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy.

Proceedings of the National Academy of Sciences of the United States of America
|October 13, 2004
PubMed

Insights

The crystal structure of human HDAC8 reveals key differences from bacterial enzymes, including potassium ion interactions crucial for fold stabilization. This finding supports HDAC8

Area of Science:

  • Biochemistry
  • Structural Biology
  • Cancer Research

Background:

  • Histone deacetylases (HDACs) regulate gene expression, DNA repair, and stress response, with altered activity in tumors.
  • HDAC inhibitors show significant antitumor activity in clinical trials.

Purpose of the Study:

  • To determine the crystal structure of human HDAC8 in complex with a hydroxamic acid inhibitor.
  • To elucidate the structural features and catalytic mechanisms of human HDAC8.

Main Methods:

  • X-ray crystallography to determine the 3D structure of human HDAC8-inhibitor complex.
  • Circular Dichroism (CD) spectroscopy to investigate the role of potassium ions.
  • RNA interference (RNAi) to assess HDAC8's role in cancer cell proliferation.

Main Results:

  • The crystal structure of eukaryotic zinc-dependent HDAC8 was determined, revealing a single alpha/beta domain.
  • Structural comparison with bacterial HDAC-like protein showed similarities in inhibitor and zinc-binding sites but differences in active site loops.
  • Two potassium ions were identified in the HDAC8 structure, with one interacting with catalytic residues, suggesting a role in fold stabilization.
  • HDAC8 knockdown inhibited the proliferation of human lung, colon, and cervical cancer cell lines.

Conclusions:

  • The unique structural features of HDAC8, including potassium ion interactions, are important for its function.
  • HDAC8 is crucial for tumor cell proliferation, making it a potential target for cancer therapy.
  • These findings facilitate the design of selective HDAC8 inhibitors for antitumor drug development.

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