2GH6

Crystal structure of a HDAC-like protein with 9,9,9-trifluoro-8-oxo-N-phenylnonan amide bound

Summary for 2GH6

• Entry DOI: 10.2210/pdb2gh6/pdb
• Related: 1ZZ0 1ZZ1 1ZZ3
• Descriptor: Histone deacetylase-like amidohydrolase, ZINC ION, POTASSIUM ION, ... (5 entities in total)
• Functional Keywords: histone deacetylase, zinc-ion, trifluoromethyl ketone, hydrolase
• Biological source: Alcaligenaceae bacterium FB188
• Total number of polymer chains: 4
• Total formula weight: 159478.04

Authors

Nielsen, T.K.,Hildmann, C.,Riester, D.,Wegener, D.,Schwienhorst, A.,Ficner, R. (deposition date: 2006-03-26, release date: 2007-03-20, Last modification date: 2023-08-30)

Primary citation

Nielsen, T.K.,Hildmann, C.,Riester, D.,Wegener, D.,Schwienhorst, A.,Ficner, R.
Complex structure of a bacterial class 2 histone deacetylase homologue with a trifluoromethylketone inhibitor.
Acta Crystallogr.,Sect.F, 63:270-273, 2007

PubMed 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.

PubMed: 17401192
DOI: 10.1107/S1744309107012377

Experimental method

X-RAY DIFFRACTION (2.203 Å)