2ao0

From Proteopedia

Revision as of 06:08, 21 November 2007

Structure of Aldehyde Reductase Holoenzyme in Complex with the Potent Aldose Reductase Inhibitor Fidarestat: Implications for Inhibitor Binding and Selectivity

Overview

Structure determination of porcine aldehyde reductase holoenzyme in, complex with the potent aldose reductase inhibitor fidarestat was carried, out to explain the difference in the potency of the inhibitor for aldose, and aldehyde reductases. The hydrogen bonds between the active-site, residues Tyr50, His113, and Trp114 and fidarestat are conserved in the two, enzymes. In aldose reductase, Leu300 forms a hydrogen bond through its, main-chain nitrogen atom with the exocyclic amide group of the inhibitor, which when replaced with a Pro in aldehyde reductase, cannot form a, hydrogen bond, thus causing a loss in binding energy. Furthermore, in, aldehyde reductase, the side chain of Trp220 occupies a disordered split, conformation that is not observed in aldose reductase. Molecular modeling, and inhibitory activity measurements suggest that the difference in the, interaction between the side chain of Trp220 and fidarestat may contribute, to the difference in the binding of the inhibitor to the enzymes.

About this Structure

2AO0 is a Single protein structure of sequence from Sus scrofa with SO4, NAP and FID as ligands. Active as Alcohol dehydrogenase (NADP(+)), with EC number 1.1.1.2 Full crystallographic information is available from OCA.

Reference

Structure of aldehyde reductase holoenzyme in complex with the potent aldose reductase inhibitor fidarestat: implications for inhibitor binding and selectivity., El-Kabbani O, Carbone V, Darmanin C, Oka M, Mitschler A, Podjarny A, Schulze-Briese C, Chung RP, J Med Chem. 2005 Aug 25;48(17):5536-42. PMID:16107153

Page seeded by OCA on Wed Nov 21 08:15:19 2007