1hsh

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spinqualitylabelsall models 1hsh, resolution 1.9Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTAL STRUCTURE AT 1.9 ANGSTROMS RESOLUTION OF HUMAN IMMUNODEFICIENCY VIRUS (HIV) II PROTEASE COMPLEXED WITH L-735,524, AN ORALLY BIOAVAILABLE INHIBITOR OF THE HIV PROTEASES

Overview

L-735,524 is a potent, orally bioavailable inhibitor of human, immunodeficiency virus (HIV) protease currently in a Phase II clinical, trial. We report here the three-dimensional structure of L-735,524, complexed to HIV-2 protease at 1.9-A resolution, as well as the structure, of the native HIV-2 protease at 2.5-A resolution. The structure of HIV-2, protease is found to be essentially identical to that of HIV-1 protease., In the crystal lattice of the HIV-2 protease complexed with L-735,524, the, inhibitor is chelated to the active site of the homodimeric enzyme in one, orientation. This feature allows an unambiguous assignment of, protein-ligand interactions from the electron density map. Both Fourier, and difference Fourier maps reveal clearly the closure of the flap domains, of the protease upon L-735,524 binding. Specific interactions between the, enzyme and the inhibitor include the hydroxy group of the, hydroxyaminopentane amide moiety of L-735,524 ligating to the carboxyl, groups of the essential Asp-25 and Asp-25' enzymic residues and the amide, oxygens of the inhibitor hydrogen bonding to the backbone amide nitrogen, of Ile-50 and Ile-50' via an intervening water molecule. A second bridging, water molecule is found between the amide nitrogen N2 of L-735,524 and the, carboxyl oxygen of Asp-29'. Although other hydrogen bonds also add to, binding, an equally significant contribution to affinity arises from, hydrophobic interactions between the protease and the inhibitor throughout, the pseudo-symmetric S1/S1', S2/S2', and S3/S3' regions of the enzyme., Except for its pyridine ring, all lipophilic moieties (t-butyl, indanyl, benzyl, and piperidyl) of L-735,524 are rigidly defined in the active, site.

About this Structure

1HSH is a Single protein structure of sequence from Human immunodeficiency virus 1 with MK1 as ligand. Full crystallographic information is available from OCA.

Reference

Crystal structure at 1.9-A resolution of human immunodeficiency virus (HIV) II protease complexed with L-735,524, an orally bioavailable inhibitor of the HIV proteases., Chen Z, Li Y, Chen E, Hall DL, Darke PL, Culberson C, Shafer JA, Kuo LC, J Biol Chem. 1994 Oct 21;269(42):26344-8. PMID:7929352

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