2nnp
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Crystal structure analysis of HIV-1 protease mutant I84V with a inhibitor saquinavir
OverviewOverview
Saquinavir (SQV), the first antiviral HIV-1 protease (PR) inhibitor, approved for AIDS therapy, has been studied in complexes with PR and the, variants PR(I) (84V) and PR(V) (82A) containing the single mutations I84V, and V82A that provide resistance to all the clinical inhibitors. Atomic, resolution crystal structures (0.97-1.25 A) of the SQV complexes were, analyzed in comparison to the protease complexes with darunavir, a new, drug that targets resistant HIV, in order to understand the molecular, basis of drug resistance. PR(I) (84V) and PR(V) (82A) complexes were, obtained in both the space groups P2(1)2(1)2 and P2(1)2(1)2(1), which, provided experimental limits for the conformational flexibility. The SQV, interactions with PR were very similar in the mutant complexes, consistent, with the similar inhibition constants. The mutation from bigger to smaller, amino acids allows more space to accommodate the large group at P1' of, SQV, unlike the reduced interactions observed in darunavir complexes. The, residues 79-82 have adjusted to accommodate the large hydrophobic groups, of SQV, suggesting that these residues are intrinsically flexible and, their conformation depends more on the nature of the inhibitor than on the, mutations in this region. This analysis will assist with development of, more effective antiviral inhibitors. Proteins 2007. (c) 2007 Wiley-Liss, Inc.
About this StructureAbout this Structure
2NNP is a Single protein structure of sequence from Human immunodeficiency virus 1 with , , and as ligands. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.
ReferenceReference
Atomic resolution crystal structures of HIV-1 protease and mutants V82A and I84V with saquinavir., Tie Y, Kovalevsky AY, Boross P, Wang YF, Ghosh AK, Tozser J, Harrison RW, Weber IT, Proteins. 2007 Jan 22;67(1):232-242. PMID:17243183
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