Open AccessComplex structure of a bacterial class 2 histone deacetylase homologue with a trifluoromethylketone inhibitor
Author(s) -
Nielsen Tine Kragh,
Hildmann Christian,
Riester Daniel,
Wegener Dennis,
Schwienhorst Andreas,
Ficner Ralf
Publication year - 2007
Publication title -
acta crystallographica section f
Language(s) - English
Resource type - Journals
ISSN - 1744-3091
DOI - 10.1107/s1744309107012377
Subject(s) - amidohydrolase , hydroxamic acid , histone deacetylase , enzyme , chemistry , stereochemistry , homology modeling , biochemistry , active site , moiety , histone , gene
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.