The structure of alclehyde reductase (ALR1) in ternary complex with the coenzyme NADPH and 3,5-dichlorosalicylic acid (DCL), a potent inhibitor of human 20 alpha-hydroxysteroid dehydrogenase (AKR1C1), was determined at a resolution of 2.41 angstrom. The inhibitor formed a network of hydrogen bonds with the active site residues Trp22, Tyt50, His113, Trpl 14 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. (c) 2008 Elsevier Inc. All rights reserved.
|Pages (from-to)||82 - 87|
|Number of pages||6|
|Journal||Archives of Biochemistry and Biophysics|
|Publication status||Published - 2008|