Refined 1.8 Å Structure of Human Aldose Reductase Complexed with the Potent Inhibitor Zopolrestat

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 90; no. 21; pp. 9847 - 9851
• Main Authors: Wilson, David K., Tarle, Ivan, Petrash, J. Mark, Quiocho, Florante A.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01.11.1993; National Acad Sciences; National Academy of Sciences
• Subjects: Active sites; Aldehyde Reductase - antagonists & inhibitors; Aldehyde Reductase - chemistry; Amino Acid Sequence; Atoms; Benzothiazoles; Binding Sites; Biochemistry; Biological and medical sciences; Carboxylates; Coenzymes; Diabetes complications; Enzymes; General and cellular metabolism. Vitamins; Humans; Hydrogen bonds; Medical sciences; Models, Molecular; Molecular Structure; Molecules; NADP - metabolism; Pharmacology. Drug treatments; Phthalazines - chemistry; Phthalazines - metabolism; Protein Conformation; Protein Structure, Secondary; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - chemistry; Thiazoles - chemistry; Thiazoles - metabolism; X-Ray Diffraction - methods; X-rays; Endocrinopathy; Human; Enzyme; Diabetes mellitus; Enzyme inhibitor; Inhibitor enzyme complex; Treatment; Structure activity relation; Aldehyde reductase; Complication; Oxidoreductases; Structural analysis; Crystalline structure
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.90.21.9847

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 Å 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 (≤4 Å) 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.