Abstract
Human aldo-keto reductase 1B10 (AKR1B10) is overexpressed in many cancer types and is involved in chemoresistance. This makes AKR1B10 to be an interesting drug target and thus many enzyme inhibitors have been investigated. High-resolution crystallographic structures of AKR1B10 with various reversible inhibitors were deeply analyzed and compared to those of analogous complexes with aldose reductase (AR). In both enzymes, the active site included an anion-binding pocket and, in some cases, inhibitor binding caused the opening of a transient specificity pocket. Different structural conformers were revealed upon inhibitor binding, emphasizing the importance of the highly variable loops, which participate in the transient opening of additional binding subpockets. Two key differences between AKR1B10 and AR were observed regarding the role of external loops in inhibitor binding. The first corresponded to the alternative conformation of Trp112 (Trp111 in AR). The second difference dealt with loop A mobility, which defined a larger and more loosely packed subpocket in AKR1B10. From this analysis, the general features that a selective AKR1B10 inhibitor should comply with are the following: an anchoring moiety to the anion-binding pocket, keeping Trp112 in its native conformation (AKR1B10-like), and not opening the specificity pocket in AR.
Highlights
Aldo-keto reductases (AKRs) constitute a superfamily of NADP(H)-dependent, monomeric oxidoreductases, mostly cytosolic, catalyzing the reduction of carbonyl-containing compounds to their corresponding alcohols
Different protein conformers may contribute to inhibitor selectivity against aldo-keto reductase 1B10 (AKR1B10) versus aldose reductase (AR)
Due to the flexibility of the AKR1B10 active site and the existence of transient opening subpockets, the exact inhibitor-AKR1B10 interactions might need to be determined on a case-by-case basis using crystallographic methods
Summary
Aldo-keto reductases (AKRs) constitute a superfamily of NADP(H)-dependent, monomeric oxidoreductases, mostly cytosolic, catalyzing the reduction of carbonyl-containing compounds to their corresponding alcohols. An elevated number of high-quality crystallographic AKR structures (AKR1B1, 156; AKR1B10, 20) are available from the Protein Data Bank (PDB), some with a resolution higher than 1 Å, and many including ternary complexes with inhibitors. This makes AKR superfamily to be one of the best-known enzyme systems at atomic level with a well-established catalytic mechanism. His110, Trp111 and the nicotinamide moiety of NADP+ define a geometrically rigid “anionbinding pocket” (ABP) The existence of this pocket was originally established from the structures of the complexes of AKR1B1 with citrate, cacodylate and glucose-6-phosphate. We provide some hints for structure-based drug design of more selective AKR1B10 inhibitors
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