1w22

From Proteopedia

Revision as of 16:17, 18 December 2007

CRYSTAL STRUCTURE OF INHIBITED HUMAN HDAC8

Overview

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.

About this Structure

1W22 is a Single protein structure of sequence from Homo sapiens with ZN, K and NHB as ligands. Known structural/functional Site: . Full crystallographic information is available from OCA.

Reference

Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor., Vannini A, Volpari C, Filocamo G, Casavola EC, Brunetti M, Renzoni D, Chakravarty P, Paolini C, De Francesco R, Gallinari P, Steinkuhler C, Di Marco S, Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15064-9. Epub 2004 Oct 11. PMID:15477595

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