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Refined 1.8 A structure of human aldose reductase complexed with the potent inhibitor zopolrestat
D K Wilson1, I Tarle, J M Petrash
1Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030.
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.
Insights
Researchers elucidated the 3D structure of human aldose reductase complexed with zopolrestat, a potent inhibitor. This structural insight aids in understanding diabetic complications and designing new therapeutics.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- Aldose reductase (EC 1.1.1.21) is implicated in diabetic complications affecting the nervous, renal, and visual systems.
- Developing therapeutic agents targeting aldose reductase is a significant research focus.
Purpose of the Study:
- To determine the refined X-ray structure of the human aldose reductase holoenzyme.
- To investigate the binding mode of zopolrestat, a potent noncompetitive inhibitor.
Main Methods:
- X-ray crystallography was used to obtain the refined 1.8 A structure.
- Analysis of the complex formed between human aldose reductase and zopolrestat.
Main Results:
- Zopolrestat binds within the hydrophobic active site pocket, inducing a hinge-flap motion that closes the pocket.
- The binding involves extensive interactions, including 110 contacts with residues, the NADPH coenzyme, and water molecules.
- High complementarity and affinity were observed upon inhibitor binding.
Conclusions:
- The determined structure provides critical insights into the mechanism of action for this class of aldose reductase inhibitors.
- This structural information is valuable for the rational design of improved therapeutic agents for diabetic complications.