title: Structure of aldehyde reductase in ternary complex with coenzyme and the potent 20alpha-hydroxysteroid dehydrogenase inhibitor 3,5-dichlorosalicylic acid: implications for inhibitor binding and selectivity.
abstract: The structure of aldehyde reductase (ALR1) in ternary complex with the coenzyme NADPH and 3,5-dichlorosalicylic acid (DCL), a potent inhibitor of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1), was determined at a resolution of 2.41A. The inhibitor formed a network of hydrogen bonds with the active site residues Trp22, Tyr50, His113, Trp114 and Arg312. Molecular modelling calculations together with inhibitory activity measurements indicated that DCL was a less potent inhibitor of ALR1 (256-fold) when compared to AKR1C1. In AKR1C1, the inhibitor formed a 10-fold stronger binding interaction with the catalytic residue (Tyr55), non-conserved hydrogen bonding interaction with His222, and additional van der Waals contacts with the non-conserved C-terminal residues Leu306, Leu308 and Phe311 that contribute to the inhibitor's selectivity advantage for AKR1C1 over ALR1.
authors.affiliation: Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Carbone
authors.forename: Roland
authors.initials: R
authors.lastname: Chung
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
authors.forename: Ossama
authors.initials: O
authors.lastname: El-Kabbani
mesh_terms: D000449:Aldehyde Reductase / Q000032:analysis / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D002723:Chlorobenzoates; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D015394:Molecular Structure; D009249:NADP / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012459:Salicylates / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013552:Swine; D014961:X-Ray Diffraction
chemical_list: D002723:Chlorobenzoates; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D012459:Salicylates; D009249:NADP; D000449:Aldehyde Reductase; C514856:3,5-dichlorosalicylic acid