title: Structural insights into the neuroprotective-acting carbonyl reductase Sniffer of Drosophila melanogaster.
abstract: In vivo studies with the fruit-fly Drosophila melanogaster have shown that the Sniffer protein prevents age-dependent and oxidative stress-induced neurodegenerative processes. Sniffer is a NADPH-dependent carbonyl reductase belonging to the enzyme family of short-chain dehydrogenases/reductases (SDRs). The crystal structure of the homodimeric Sniffer protein from Drosophila melanogaster in complex with NADP+ has been determined by multiple-wavelength anomalous dispersion and refined to a resolution of 1.75 A. The observed fold represents a typical dinucleotide-binding domain as detected for other SDRs. With respect to the cofactor-binding site and the region referred to as substrate-binding loop, the Sniffer protein shows a striking similarity to the porcine carbonyl reductase (PTCR). This loop, in both Sniffer and PTCR, is substantially shortened compared to other SDRs. In most enzymes of the SDR family this loop adopts a well-defined conformation only after substrate binding and remains disordered in the absence of any bound ligands or even if only the dinucleotide cofactor is bound. In the structure of the Sniffer protein, however, the conformation of this loop is well defined, although no substrate is present. Molecular modeling studies provide an idea of how binding of substrate molecules to Sniffer could possibly occur.
authors.affiliation: Institute of Pharmaceutical Chemistry, University of Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Sgraja
authors.forename: Julia
authors.initials: J
authors.lastname: Ulschmid
authors.forename: Katja
authors.initials: K
authors.lastname: Becker
authors.forename: Stephan
authors.initials: S
authors.lastname: Schneuwly
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
authors.forename: Klaus
authors.initials: K
authors.lastname: Reuter
authors.forename: Andreas
authors.initials: A
authors.lastname: Heine
mesh_terms: D000429:Alcohol Oxidoreductases / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003460:Crystallization; D018360:Crystallography, X-Ray; D029721:Drosophila Proteins / Q000737:chemistry* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000201:enzymology*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009249:NADP / Q000737:chemistry / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013552:Swine
chemical_list: D029721:Drosophila Proteins; D008024:Ligands; D018696:Neuroprotective Agents; D009249:NADP; C487696:sni protein, Drosophila; D000429:Alcohol Oxidoreductases