2NNP

Crystal structure analysis of HIV-1 protease mutant I84V with a inhibitor saquinavir

Summary for 2NNP

• Entry DOI: 10.2210/pdb2nnp/pdb
• Related: 2NMW 2NMY 2NMZ 2NNK
• Related PRD ID: PRD_000454
• Descriptor: PROTEASE, (2S)-N-[(2S,3R)-4-[(2S,3S,4aS,8aS)-3-(tert-butylcarbamoyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-3-hydroxy-1 -phenyl-butan-2-yl]-2-(quinolin-2-ylcarbonylamino)butanediamide, ACETIC ACID, ... (6 entities in total)
• Functional Keywords: hiv-1 protease, mutant, i84v, dimer, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Cellular location: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P04587
• Total number of polymer chains: 2
• Total formula weight: 22524.50

Authors

Tie, Y.,Kovalevsky, A.Y.,Boross, P.,Wang, Y.F.,Ghosh, A.K.,Tozser, J.,Harrison, R.W.,Weber, I.T. (deposition date: 2006-10-24, release date: 2007-03-13, Last modification date: 2023-12-27)

Primary citation

Tie, Y.,Kovalevsky, A.Y.,Boross, P.,Wang, Y.F.,Ghosh, A.K.,Tozser, J.,Harrison, R.W.,Weber, I.T.
Atomic resolution crystal structures of HIV-1 protease and mutants V82A and I84V with saquinavir.
Proteins, 67:232-242, 2007

PubMed Abstract: 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.

PubMed: 17243183
DOI: 10.1002/prot.21304

Experimental method

X-RAY DIFFRACTION (1.2 Å)