Structure of rat aldose reductase-like protein AKR1B14 holoenzyme: Probing the role of His269 in coenzyme binding by site-directed mutagenesis

Krithika Sundaram, Urmi Dhagat, Satoshi Endo, Roland Chung, Toshiyuki Matsunaga, Akira Hara, Ossama El-Kabbani

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Rat aldose reductase-like protein (AKR1B14) is the ortholog of mouse vas deferens protein (AKR1B7) playing roles in detoxification of reactive aldehydes and synthesis of prostaglandin F2I?. The crystal structure of the binary complex (AKR1B14-NADPH) was determined at 1.86 ?? resolution, and showed that the adenine ring and the 2a??-phosphate group of the coenzyme formed I?-stacking and electrostatic interactions with the imidazole ring and ND1 atom, respectively, of His269, which is not conserved in other aldose reductase-like proteins. The interactions were supported by site-directed mutagenesis of His269 to Arg, Phe and Met, which increased the Km for NADPH by 4, 7 and 127-fold, respectively. This is the first report of the tertiary structure of a rodent AKR1B7 ortholog, which describes the role of a novel dual interaction for the non-conserved His269 in coenzyme binding.
Original languageEnglish
Pages (from-to)801 - 804
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Issue number2
Publication statusPublished - 2011

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