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

David K. Wilson, Ivan Tarle, J. Mark Petrash, Florante A. Quiocho

Research output: Contribution to journalArticle

205 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)9847-9851
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume90
Issue number21
StatePublished - Nov 1 1993
Externally publishedYes

Keywords

  • Active site
  • Diabetic complications
  • Drug design

ASJC Scopus subject areas

  • General
  • Genetics

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