title: Complex structure of a bacterial class 2 histone deacetylase homologue with a trifluoromethylketone inhibitor.
abstract: 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.
authors.affiliation: Abteilung für Molekulare Strukturbiologie, Institut für Mikrobiologie und Genetik and GZMB, Justus-von-Liebig Weg 11, 37077 Göttingen, Germany.
authors.forename: Tine Kragh
authors.initials: TK
authors.lastname: Nielsen
authors.forename: Christian
authors.initials: C
authors.lastname: Hildmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Riester
authors.forename: Dennis
authors.initials: D
authors.lastname: Wegener
authors.forename: Andreas
authors.initials: A
authors.lastname: Schwienhorst
authors.forename: Ralf
authors.initials: R
authors.lastname: Ficner
mesh_terms: D000818:Animals; D003460:Crystallization; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry*; D007659:Ketones / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D011487:Protein Conformation; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D007659:Ketones; D006655:Histone Deacetylases