The alrestatin double-decker: binding of two inhibitor molecules to human aldose reductase reveals a new specificity determinant. Academic Article uri icon

Overview

abstract

  • It is generally expected that only one inhibitor molecule will bind to an enzyme active site. In fact, specific drug design theories depend upon this assumption. Here, we report the binding of two molecules of an inhibitor to the same active site which we observed in the 1.8 A resolution structure of the drug Alrestatin bound to a mutant of human aldose reductase. The two molecules of Alrestatin bind to the active site in a stacked arrangement (a double-decker). This stack positions the carboxylic acid of one drug molecule near the NADP+ cofactor at a previously determined anion binding site and the carboxylic acid of the second drug molecule near the carboxy-terminal tail of the enzyme. We propose that interactions of inhibitors with the carboxy-terminal loop of aldose reductase are critical for the development of inhibitors that are able to discriminate between aldose reductase and other members of the aldo-keto reductase superfamily. This finding suggests a new direction for the introduction of specificity to aldose reductase-targeted drugs.

publication date

  • December 23, 1997

Research

keywords

  • Aldehyde Reductase
  • Isoquinolines

Identity

Scopus Document Identifier

  • 0031424157

Digital Object Identifier (DOI)

  • 10.1021/bi9717136

PubMed ID

  • 9405046

Additional Document Info

volume

  • 36

issue

  • 51