TY - JOUR
T1 - 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
AU - Carbone, Vincenzo
AU - Chung, Roland Poh-Tuck
AU - Endo, Satoshi
AU - Hara, Akira
AU - El-Kabbani, Ossama
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
UR - http://www.sciencedirect.com/science/article/pii/S0003986108004104
M3 - Article
SN - 0003-9861
VL - 479
SP - 82
EP - 87
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
IS - 1
ER -