Crystal Structure of a Eukaryotic Zinc-dependent Histone Deacetylase, Human HDAC8, Complexed with a Hydroxamic Acid Inhibitor

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2004 Oct 13

PMID 15477595

Citations 218

Authors

Alessandro Vannini

Cinzia Volpari

Gessica Filocamo

Elena Caroli Casavola

Mirko Brunetti

Debora Renzoni

Prasun Chakravarty

Chantal Paolini

Raffaele De Francesco

Paola Gallinari

Christian Steinkuhler

Stefania Di Marco

Affiliations

Soon will be listed here.

Abstract

Histone deacetylases (HDACs) are a family of enzymes involved in the regulation of gene expression, DNA repair, and stress response. These processes often are altered in tumors, and HDAC inhibitors have had pronounced antitumor activity with promising results in clinical trials. Here, we report the crystal structure of human HDAC8 in complex with a hydroxamic acid inhibitor. Such a structure of a eukaryotic zinc-dependent HDAC has not be described previously. Similar to bacterial HDAC-like protein, HDAC8 folds in a single alpha/beta domain. The inhibitor and the zinc-binding sites are similar in both proteins. However, significant differences are observed in the length and structure of the loops surrounding the active site, including the presence of two potassium ions in HDAC8 structure, one of which interacts with key catalytic residues. CD data suggest a direct role of potassium in the fold stabilization of HDAC8. Knockdown of HDAC8 by RNA interference inhibits growth of human lung, colon, and cervical cancer cell lines, highlighting the importance of this HDAC subtype for tumor cell proliferation. Our findings open the way for the design and development of selective inhibitors of HDAC8 as possible antitumor agents.

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