Structural Basis for the Inhibition of AKR1B10 by Caffeic Acid Phenethyl Ester ( CAPE)

Caffeic acid phenethyl ester (CAPE), the major bioactive component of honeybee propolis, is a potent selective inhibitor of aldo-keto reductase family member1B10 (AKR1B10), and a number of derivatives hold promise as potential anticancer agents. However, sequence homology between AKR1B10 and other members of the superfamily, including critical phaseI metabolizing enzymes, has resulted in a concern over the selectivity of any potential therapeutic agent. To elucidate the binding mode of CAPE with AKR1B10 and to provide a tool for future in silico efforts towards identifying selective inhibitors, the crystal structure of AKR1B10 in complex with CAPE was determined. The observed interactions provide an explanation for the selectivity exhibited by CAPE for AKR1B10, and could be used to guide further derivative design.