Structure of aldehyde reductase in ternary complex with coenzyme and the potent 20α-hydroxysteroid dehydrogenase inhibitor 3,5-dichlorosalicylic acid: Implications for inhibitor binding and selectivity
Copyright policy )Structure of aldehyde reductase in ternary complex with coenzyme and the potent 20α-hydroxysteroid dehydrogenase inhibitor 3,5-dichlorosalicylic acid: Implications for inhibitor binding and selectivity
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.
- Institute of Pharmaceutical Sciences Switzerland
- Gifu Pharmaceutical University Japan
Models, Molecular, Binding Sites, Molecular Structure, Swine, Hydrogen Bonding, Hydrogen-Ion Concentration, Crystallography, X-Ray, Protein Structure, Secondary, Recombinant Proteins, Salicylates, Protein Structure, Tertiary, Chlorobenzoates, X-Ray Diffraction, Aldehyde Reductase, Animals, Enzyme Inhibitors, NADP, Protein Binding
Models, Molecular, Binding Sites, Molecular Structure, Swine, Hydrogen Bonding, Hydrogen-Ion Concentration, Crystallography, X-Ray, Protein Structure, Secondary, Recombinant Proteins, Salicylates, Protein Structure, Tertiary, Chlorobenzoates, X-Ray Diffraction, Aldehyde Reductase, Animals, Enzyme Inhibitors, NADP, Protein Binding
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