1MAR

REFINED 1.8 ANGSTROMS STRUCTURE OF HUMAN ALDOSE REDUCTASE COMPLEXED WITH THE POTENT INHIBITOR ZOPOLRESTAT

Summary for 1MAR

• Entry DOI: 10.2210/pdb1mar/pdb
• Descriptor: ALDOSE REDUCTASE, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 3,4-DIHYDRO-4-OXO-3-((5-TRIFLUOROMETHYL-2-BENZOTHIAZOLYL)METHYL)-1-PHTHALAZINE ACETIC ACID (3 entities in total)
• Functional Keywords: oxidoreductase(nadp)
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P15121
• Total number of polymer chains: 1
• Total formula weight: 36929.93

Authors

Wilson, D.K.,Quiocho, F.A. (deposition date: 1993-07-20, release date: 1995-07-20, Last modification date: 2024-02-14)

Primary citation

Wilson, D.K.,Tarle, I.,Petrash, J.M.,Quiocho, F.A.
Refined 1.8 A structure of human aldose reductase complexed with the potent inhibitor zopolrestat.
Proc.Natl.Acad.Sci.USA, 90:9847-9851, 1993

PubMed 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.

PubMed: 8234324
DOI: 10.1073/pnas.90.21.9847

Experimental method

X-RAY DIFFRACTION (1.8 Å)