title: Structure of aldehyde reductase holoenzyme in complex with the potent aldose reductase inhibitor fidarestat: implications for inhibitor binding and selectivity.
abstract: Structure determination of porcine aldehyde reductase holoenzyme in complex with the potent aldose reductase inhibitor fidarestat was carried out to explain the difference in the potency of the inhibitor for aldose and aldehyde reductases. The hydrogen bonds between the active-site residues Tyr50, His113, and Trp114 and fidarestat are conserved in the two enzymes. In aldose reductase, Leu300 forms a hydrogen bond through its main-chain nitrogen atom with the exocyclic amide group of the inhibitor, which when replaced with a Pro in aldehyde reductase, cannot form a hydrogen bond, thus causing a loss in binding energy. Furthermore, in aldehyde reductase, the side chain of Trp220 occupies a disordered split conformation that is not observed in aldose reductase. Molecular modeling and inhibitory activity measurements suggest that the difference in the interaction between the side chain of Trp220 and fidarestat may contribute to the difference in the binding of the inhibitor to the enzymes.
authors.affiliation: Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University (Parkville Campus), 381 Royal Parade, Vic 3052, Australia. Ossama.El-Kabbani@ vcp.monash.edu.au
authors.forename: Ossama
authors.initials: O
authors.lastname: El-Kabbani
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Carbone
authors.forename: Connie
authors.initials: C
authors.lastname: Darmanin
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Oka
authors.forename: Andre
authors.initials: A
authors.lastname: Mitschler
authors.forename: Alberto
authors.initials: A
authors.lastname: Podjarny
authors.forename: Clemens
authors.initials: C
authors.lastname: Schulze-Briese
authors.forename: Roland P-T
authors.initials: RP
authors.lastname: Chung
mesh_terms: D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D020035:Holoenzymes / Q000737:chemistry; D048289:Imidazolidines / Q000737:chemistry*; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D020035:Holoenzymes; D048289:Imidazolidines; C077139:fidarestat; D000429:Alcohol Oxidoreductases; C019642:alcohol dehydrogenase (NADP+); D000449:Aldehyde Reductase; C026411:sorbinil