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Refined 1.8 A structure of human aldose reductase complexed with the potent inhibitor zopolrestat.

ABSTRACT: As the action of aldose reductase (EC 1.1.1.21) is believed to be linked to the pathogenesis of diabetic complications affecting the nervous, renal, and visual systems, the development of therapeutic agents has attracted intense effort. We report the refined 1.8 A x-ray structure of the human holoenzyme complexed with zopolrestat, one of the most potent noncompetitive inhibitors. The zopolrestat fits snugly in the hydrophobic active site pocket and induces a hinge-flap motion of two peptide segments that closes the pocket. Excellent complementarity and affinity are achieved on inhibitor binding by the formation of 110 contacts (< or = 4 A) with 15 residues (10 hydrophobic), 13 with the NADPH coenzyme and 9 with four water molecules. The structure is key to understanding the mode of action of this class of inhibitors and for rational design of better therapeutics.

SUBMITTER: Wilson DK

PROVIDER: S-EPMC47669 | biostudies-other | 1993 Nov

REPOSITORIES: biostudies-other

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Refined 1.8 A structure of human aldose reductase complexed with the potent inhibitor zopolrestat.

Wilson D K DK Tarle I I Petrash J M JM Quiocho F A FA

Proceedings of the National Academy of Sciences of the United States of America 19931101 21

As the action of aldose reductase (EC 1.1.1.21) is believed to be linked to the pathogenesis of diabetic complications affecting the nervous, renal, and visual systems, the development of therapeutic agents has attracted intense effort. We report the refined 1.8 A x-ray structure of the human holoenzyme complexed with zopolrestat, one of the most potent noncompetitive inhibitors. The zopolrestat fits snugly in the hydrophobic active site pocket and induces a hinge-flap motion of two peptide segm ...[more]

PMID: 8234324

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