1us0

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spinqualitylabelsall models 1us0, resolution 0.66Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

HUMAN ALDOSE REDUCTASE IN COMPLEX WITH NADP+ AND THE INHIBITOR IDD594 AT 0.66 ANGSTROM

Overview

The first subatomic resolution structure of a 36 kDa protein [aldose, reductase (AR)] is presented. AR was cocrystallized at pH 5.0 with its, cofactor NADP+ and inhibitor IDD 594, a therapeutic candidate for the, treatment of diabetic complications. X-ray diffraction data were collected, up to 0.62 A resolution and treated up to 0.66 A resolution. Anisotropic, refinement followed by a blocked matrix inversion produced low standard, deviations (<0.005 A). The model was very well ordered overall (CA atoms', mean B factor is 5.5 A2). The model and the electron-density maps revealed, fine features, such as H-atoms, bond densities, and significant deviations, from standard stereochemistry. Other features, such as networks of, hydrogen bonds (H bonds), a large number of multiple conformations, and, solvent structure were also better defined. Most of the atoms in the, active site region were extremely well ordered (mean B approximately 3, A2), leading to the identification of the protonation states of the, residues involved in catalysis. The electrostatic interactions of the, inhibitor's charged carboxylate head with the catalytic residues and the, charged coenzyme NADP+ explained the inhibitor's noncompetitive character., Furthermore, a short contact involving the IDD 594 bromine atom explained, the selectivity profile of the inhibitor, important feature to avoid toxic, effects. The presented structure and the details revealed are instrumental, for better understanding of the inhibition mechanism of AR by IDD 594, and, hence, for the rational drug design of future inhibitors. This work, demonstrates the capabilities of subatomic resolution experiments and, stimulates further developments of methods allowing the use of the full, potential of these experiments.

About this Structure

1US0 is a Single protein structure of sequence from Homo sapiens with NDP, LDT 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.

Reference

Ultrahigh resolution drug design I: details of interactions in human aldose reductase-inhibitor complex at 0.66 A., Howard EI, Sanishvili R, Cachau RE, Mitschler A, Chevrier B, Barth P, Lamour V, Van Zandt M, Sibley E, Bon C, Moras D, Schneider TR, Joachimiak A, Podjarny A, Proteins. 2004 Jun 1;55(4):792-804. PMID:15146478

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