title: Factorizing selectivity determinants of inhibitor binding toward aldose and aldehyde reductases: structural and thermodynamic properties of the aldose reductase mutant Leu300Pro-fidarestat complex.
abstract: Structure of the Leu300Pro mutant of human aldose reductase (ALR2) in complex with the inhibitor fidarestat is determined. Comparison with the hALR2-fidarestat complex and the porcine aldehyde reductase (ALR1)-fidarestat complex indicates that the hydrogen bond between the Leu300 amino group of the wild-type and the exocyclic amide group of the inhibitor is the key determinant for the specificity of fidarestat for ALR2 over ALR1. Thermodynamic data also suggest an enthalpic contribution as the predominant difference in the binding energy between the aldose reductase mutant and the wild-type. An additional selectivity-determining feature is the difference in the interaction between the inhibitor and the side chain of Trp219, ordered in the present structure but disordered (corresponding Trp220) in the ALR1-fidarestat complex. Thus, the hydrogen bond ( approximately 7 kJ/mol) corresponds to a 23-fold difference in inhibitor potency while the differences in the interactions between Trp219(ALR2) and fidarestat and between Trp220(ALR1) and fidarestat can account for an additional 10-fold difference in potency.
authors.affiliation: Laboratoire de Génomique et de Biologie Structurales, UMR 7104 du CNRS, IGBMC, 1 Rue Laurent Fries, B.P. 10142, 67404 Illkirch, France.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Petrova
authors.forename: Holger
authors.initials: H
authors.lastname: Steuber
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hazemann
authors.forename: Alexandra
authors.initials: A
authors.lastname: Cousido-Siah
authors.forename: Andre
authors.initials: A
authors.lastname: Mitschler
authors.forename: Roland
authors.initials: R
authors.lastname: Chung
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Oka
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
authors.forename: Ossama
authors.initials: O
authors.lastname: El-Kabbani
authors.forename: Andrzej
authors.initials: A
authors.lastname: Joachimiak
authors.forename: Alberto
authors.initials: A
authors.lastname: Podjarny
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D001665:Binding Sites; D002151:Calorimetry; D003460:Crystallization; D020035:Holoenzymes / Q000737:chemistry / Q000235:genetics; D006801:Humans; D048289:Imidazolidines / Q000737:chemistry*; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D013816:Thermodynamics
chemical_list: D020035:Holoenzymes; D048289:Imidazolidines; C077139:fidarestat; C484670:AKR1B1 protein, human; D000449:Aldehyde Reductase; C026411:sorbinil