1bvg

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Revision as of 11:48, 8 November 2007

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HIV-1 PROTEASE-DMP323 COMPLEX IN SOLUTION, NMR MINIMIZED AVERAGE STRUCTURE

Overview

The three-dimensional solution structure of the HIV-1 protease homodimer, MW 22.2 kDa, complexed to a potent, cyclic urea-based inhibitor, DMP323, is reported. This is the first solution structure of an HIV, protease/inhibitor complex that has been elucidated. Multidimensional, heteronuclear NMR spectra were used to assemble more than 4,200 distance, and angle constraints. Using the constraints, together with a hybrid, distance geometry/simulated annealing protocol, an ensemble of 28 NMR, structures was calculated having no distance or angle violations greater, than 0.3 A or 5 degrees, respectively. Neglecting residues in disordered, loops, the RMS deviation (RMSD) for backbone atoms in the family of, structures was 0.60 A relative to the average structure. The individual, NMR structures had excellent covalent geometry and stereochemistry, as did, the restrained minimized average structure. The latter structure is, similar to the 1.8-A X-ray structure of the protease/DMP323 complex (Chang, CH et al., 1995, Protein Science, submitted); the pairwise backbone RMSD, calculated for the two structures is 1.22 A. As expected, the mismatch, between the structures is greatest in the loops that are disordered and/or, flexible. The flexibility of residues 37-42 and 50-51 may be important in, facilitating substrate binding and product release, because these residues, make up the respective hinges and tips of the protease flaps. Flexibility, of residues 4-8 may play a role in protease regulation by facilitating, autolysis.

About this Structure

1BVG is a Single protein structure of sequence from Human immunodeficiency virus with DMP as ligand. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.

Reference

Three-dimensional solution structure of the HIV-1 protease complexed with DMP323, a novel cyclic urea-type inhibitor, determined by nuclear magnetic resonance spectroscopy., Yamazaki T, Hinck AP, Wang YX, Nicholson LK, Torchia DA, Wingfield P, Stahl SJ, Kaufman JD, Chang CH, Domaille PJ, Lam PY, Protein Sci. 1996 Mar;5(3):495-506. PMID:8868486

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