1zz1

From Proteopedia

Revision as of 13:41, 20 March 2008

Crystal structure of a HDAC-like protein with SAHA bound

Overview

Histone deacetylases (HDACs) are among the most promising targets in cancer therapy. However, structural information greatly enhancing the design of HDAC inhibitors as novel chemotherapeutics has not been available on class 2 HDACs so far. Here we present the structure of the bacterial FB188 HDAH (histone deacetylase-like amidohydrolase from Bordetella/Alcaligenes strain FB188) that reveals high sequential and functional homology to human class 2 HDACs. FB188 HDAH is capable to remove the acetyl moiety from acetylated histones. Several HDAC-specific inhibitors, which have been shown to inhibit tumor activity in both pre-clinical models and in clinical trials, also inhibit FB188 HDAH. We have determined the crystal structure of FB188 HDAH at a resolution of 1.6 angstroms in complex with the reaction product acetate, as well as in complex with the inhibitors suberoylanilide hydroxamic acid (SAHA) and cyclopentyle-propionyle hydroxamic acid (CypX) at a resolution of 1.57 angstroms and 1.75 angstroms, respectively. FB188 HDAH exhibits the canonical fold of class 1 HDACs and contains a catalytic zinc ion. The highest structural diversity compared to class 1 enzymes is found in loop regions especially in the area around the entrance of the active site, indicating significant differences among the acetylated proteins binding to class 1 and 2 HDACs, respectively.

About this Structure

1ZZ1 is a Single protein structure of sequence from Bordetella sp.. Full crystallographic information is available from OCA.

Reference

Crystal structure of a bacterial class 2 histone deacetylase homologue., Nielsen TK, Hildmann C, Dickmanns A, Schwienhorst A, Ficner R, J Mol Biol. 2005 Nov 18;354(1):107-20. Epub 2005 Oct 7. PMID:16242151

Page seeded by OCA on Thu Mar 20 15:41:30 2008