title: Unusual binding mode of the 2S4R stereoisomer of the potent aldose reductase cyclic imide inhibitor fidarestat (2S4S) in the 15 K crystal structure of the ternary complex refined at 0.78 A resolution: implications for the inhibition mechanism.
abstract: The structure of human aldose reductase in complex with the 2 S4 R stereoisomer of the potent inhibitor Fidarestat ((2 S,4 S)-6-fluoro-2',5'-dioxospiro-[chroman-4,4'-imidazoline]-2-carboxamide) was determined at 15 K and a resolution of 0.78 A. The structure of the complex provides experimental evidence for the inhibition mechanism in which Fidarestat is initially bound neutral and then becomes negatively charged by donating the proton at the 1'-position nitrogen of the cyclic imide ring to the N2 atom of the catalytic His110.
authors.affiliation: Department of Medicinal Chemistry, Monash University,Vic 3052, Australia.
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Zhao
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hazemann
authors.forename: Andre
authors.initials: A
authors.lastname: Mitschler
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Carbone
authors.forename: Andrzej
authors.initials: A
authors.lastname: Joachimiak
authors.forename: Steve
authors.initials: S
authors.lastname: Ginell
authors.forename: Alberto
authors.initials: A
authors.lastname: Podjarny
authors.forename: Ossama
authors.initials: O
authors.lastname: El-Kabbani
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D048289:Imidazolidines / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D013237:Stereoisomerism
chemical_list: D048289:Imidazolidines; C077139:fidarestat; C484670:AKR1B1 protein, human; D000449:Aldehyde Reductase