The antineoplastic target aldo-keto reductase family member 1B10 (AKR1B10) and the critical polyol pathway enzyme aldose reductase (AKR1B1) share high structural similarity. Crystal structures reported here reveal a surprising Trp112 native conformation stabilized by a specific Gln114-centered hydrogen bond network in the AKR1B10 holoenzyme, and suggest that AKR1B1 inhibitors could retain their binding affinities toward AKR1B10 by inducing Trp112 flip to result in an "AKR1B1-like" active site in AKR1B10, while selective AKR1B10 inhibitors can take advantage of the broader active site of AKR1B10 provided by the native Trp112 side-chain orientation.
Keywords: AKR1A1; AKR1B1; AKR1B10; Crystal structure; FLF; Inhibitor selectivity; aldehyde reductase; aldose reductase aldo–keto reductase family1 member1; aldo–keto reductase family1 member10; flufenamic acid.
Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.