Structures of dimeric dihydrodiol dehydrogenase apoenzyme and inhibitor complex: Probing the subunit interface with site-directed mutagenesis
Vincenzo Carbone
Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, Parkville, Victoria 3052, Australia
Search for more papers by this authorSatoshi Endo
Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 502-8585, Japan
Search for more papers by this authorRie Sumii
Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 502-8585, Japan
Search for more papers by this authorRoland P.-T. Chung
Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, Parkville, Victoria 3052, Australia
Search for more papers by this authorToshiyuki Matsunaga
Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 502-8585, Japan
Search for more papers by this authorAkira Hara
Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 502-8585, Japan
Search for more papers by this authorCorresponding Author
Ossama El-Kabbani
Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, Parkville, Victoria 3052, Australia
Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, Parkville, Victoria 3052, Australia===Search for more papers by this authorVincenzo Carbone
Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, Parkville, Victoria 3052, Australia
Search for more papers by this authorSatoshi Endo
Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 502-8585, Japan
Search for more papers by this authorRie Sumii
Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 502-8585, Japan
Search for more papers by this authorRoland P.-T. Chung
Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, Parkville, Victoria 3052, Australia
Search for more papers by this authorToshiyuki Matsunaga
Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 502-8585, Japan
Search for more papers by this authorAkira Hara
Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 502-8585, Japan
Search for more papers by this authorCorresponding Author
Ossama El-Kabbani
Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, Parkville, Victoria 3052, Australia
Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, Parkville, Victoria 3052, Australia===Search for more papers by this authorAbstract
Dimeric dihydrodiol dehydrogenase (DD) catalyses the nicotinamide adenine dinucleotide phosphate (NADP+)-dependent oxidation of trans-dihydrodiols of aromatic hydrocarbons to their corresponding catechols. This is the first report of the crystal structure of the dimeric enzyme determined at 2.0 Å resolution. The tertiary structure is formed by a classical dinucleotide binding fold comprising of two βαβαβ motifs at the N-terminus and an eight-stranded, predominantly antiparallel β-sheet at the C-terminus. The active-site of DD, occupied either by a glycerol molecule or the inhibitor 4-hydroxyacetophenone, is located in the C-terminal domain of the protein and maintained by a number of residues including Lys97, Trp125, Phe154, Leu158, Val161, Asp176, Leu177, Tyr180, Trp254, Phe279, and Asp280. The dimer interface is stabilized by a large number of intermolecular contacts mediated by the β-sheet of each monomer, which includes an intricate hydrogen bonding network maintained in principal by Arg148 and Arg202. Site-directed mutagenesis has demonstrated that the intact dimer is not essential for catalytic activity. The similarity between the quaternary structures of mammalian DD and glucose-fructose oxidoreductase isolated from the prokaryotic organism Zymomonas mobilis suggests that both enzymes are members of a unique family of oligomeric proteins and may share a common ancestral gene. Proteins 2008. © 2007 Wiley-Liss, Inc.
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