1az2
CITRATE BOUND, C298A/W219Y MUTANT HUMAN ALDOSE REDUCTASE
|
OverviewOverview
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.
About this StructureAbout this Structure
1AZ2 is a Single protein structure of sequence from Homo sapiens with NAP and CIT as ligands. Active as Aldehyde reductase, with EC number 1.1.1.21 Known structural/functional Site: . Full crystallographic information is available from OCA.
ReferenceReference
The alrestatin double-decker: binding of two inhibitor molecules to human aldose reductase reveals a new specificity determinant., Harrison DH, Bohren KM, Petsko GA, Ringe D, Gabbay KH, Biochemistry. 1997 Dec 23;36(51):16134-40. PMID:9405046
Page seeded by OCA on Tue Dec 18 14:24:03 2007