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Title: Complex structure of a bacterial class 2 histone deacetylase homologue with a trifluoromethylketone inhibitor

Abstract

The crystal structure of HDAH FB188 in complex with a trifluoromethylketone at 2.2 Å resolution is reported and compared to a previously determined inhibitor complex. Histone deacetylases (HDACs) have emerged as attractive targets in anticancer drug development. To date, a number of HDAC inhibitors have been developed and most of them are hydroxamic acid derivatives, typified by suberoylanilide hydroxamic acid (SAHA). Not surprisingly, structural information that can greatly enhance the design of novel HDAC inhibitors is so far only available for hydroxamic acids in complex with HDAC or HDAC-like enzymes. Here, the first structure of an enzyme complex with a nonhydroxamate HDAC inhibitor is presented. The structure of the trifluoromethyl ketone inhibitor 9,9,9-trifluoro-8-oxo-N-phenylnonanamide in complex with bacterial FB188 HDAH (histone deacetylase-like amidohydrolase from Bordetella/Alcaligenes strain FB188) has been determined. HDAH reveals high sequential and functional homology to human class 2 HDACs and a high structural homology to human class 1 HDACs. Comparison with the structure of HDAH in complex with SAHA reveals that the two inhibitors superimpose well. However, significant differences in binding to the active site of HDAH were observed. In the presented structure the O atom of the trifluoromethyl ketone moiety is within binding distance of the Znmore » atom of the enzyme and the F atoms participate in interactions with the enzyme, thereby involving more amino acids in enzyme–inhibitor binding.« less

Authors:
 [1]; ; ; ;  [2];  [1]
  1. Abteilung für Molekulare Strukturbiologie, Institut für Mikrobiologie und Genetik and GZMB, Justus-von-Liebig Weg 11, 37077 Göttingen (Germany)
  2. Abteilung für Molekulare Genetik und Präparative Molekularbiologie, Institut für Mikrobiologie und Genetik, Grisebachstrasse 8, 37077 Göttingen (Germany)
Publication Date:
OSTI Identifier:
22360304
Resource Type:
Journal Article
Resource Relation:
Journal Name: Acta Crystallographica. Section F; Journal Volume: 63; Journal Issue: Pt 4; Other Information: PMCID: PMC2330214; PMID: 17401192; PUBLISHER-ID: hv5077; OAI: oai:pubmedcentral.nih.gov:2330214; Copyright (c) International Union of Crystallography 2007; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United Kingdom
Language:
English
Subject:
75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY; ATOMS; CRYSTAL STRUCTURE; DESIGN; DISTANCE; INTERACTIONS; RESOLUTION; STRAINS

Citation Formats

Nielsen, Tine Kragh, Hildmann, Christian, Riester, Daniel, Wegener, Dennis, Schwienhorst, Andreas, and Ficner, Ralf, E-mail: rficner@gwdg.de. Complex structure of a bacterial class 2 histone deacetylase homologue with a trifluoromethylketone inhibitor. United Kingdom: N. p., 2007. Web. doi:10.1107/S1744309107012377.
Nielsen, Tine Kragh, Hildmann, Christian, Riester, Daniel, Wegener, Dennis, Schwienhorst, Andreas, & Ficner, Ralf, E-mail: rficner@gwdg.de. Complex structure of a bacterial class 2 histone deacetylase homologue with a trifluoromethylketone inhibitor. United Kingdom. doi:10.1107/S1744309107012377.
Nielsen, Tine Kragh, Hildmann, Christian, Riester, Daniel, Wegener, Dennis, Schwienhorst, Andreas, and Ficner, Ralf, E-mail: rficner@gwdg.de. Sun . "Complex structure of a bacterial class 2 histone deacetylase homologue with a trifluoromethylketone inhibitor". United Kingdom. doi:10.1107/S1744309107012377.
@article{osti_22360304,
title = {Complex structure of a bacterial class 2 histone deacetylase homologue with a trifluoromethylketone inhibitor},
author = {Nielsen, Tine Kragh and Hildmann, Christian and Riester, Daniel and Wegener, Dennis and Schwienhorst, Andreas and Ficner, Ralf, E-mail: rficner@gwdg.de},
abstractNote = {The crystal structure of HDAH FB188 in complex with a trifluoromethylketone at 2.2 Å resolution is reported and compared to a previously determined inhibitor complex. Histone deacetylases (HDACs) have emerged as attractive targets in anticancer drug development. To date, a number of HDAC inhibitors have been developed and most of them are hydroxamic acid derivatives, typified by suberoylanilide hydroxamic acid (SAHA). Not surprisingly, structural information that can greatly enhance the design of novel HDAC inhibitors is so far only available for hydroxamic acids in complex with HDAC or HDAC-like enzymes. Here, the first structure of an enzyme complex with a nonhydroxamate HDAC inhibitor is presented. The structure of the trifluoromethyl ketone inhibitor 9,9,9-trifluoro-8-oxo-N-phenylnonanamide in complex with bacterial FB188 HDAH (histone deacetylase-like amidohydrolase from Bordetella/Alcaligenes strain FB188) has been determined. HDAH reveals high sequential and functional homology to human class 2 HDACs and a high structural homology to human class 1 HDACs. Comparison with the structure of HDAH in complex with SAHA reveals that the two inhibitors superimpose well. However, significant differences in binding to the active site of HDAH were observed. In the presented structure the O atom of the trifluoromethyl ketone moiety is within binding distance of the Zn atom of the enzyme and the F atoms participate in interactions with the enzyme, thereby involving more amino acids in enzyme–inhibitor binding.},
doi = {10.1107/S1744309107012377},
journal = {Acta Crystallographica. Section F},
number = Pt 4,
volume = 63,
place = {United Kingdom},
year = {Sun Apr 01 00:00:00 EDT 2007},
month = {Sun Apr 01 00:00:00 EDT 2007}
}