3N3I

Crystal Structure of G48V/C95F tethered HIV-1 Protease/Saquinavir complex

Summary for 3N3I

• Entry DOI: 10.2210/pdb3n3i/pdb
• 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 (3 entities in total)
• Functional Keywords: hiv-1 protease, saquinavir, drug resistance, tethered-dimer, fusion protein, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus type 1 (HIV-1); More
• 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 : P04585
• Total number of polymer chains: 1
• Total formula weight: 22749.83

Authors

Prashar, V.,Bihani, S.C.,Das, A.,Rao, D.R.,Hosur, M.V. (deposition date: 2010-05-20, release date: 2010-06-09, Last modification date: 2024-03-20)

Primary citation

Prashar, V.,Bihani, S.C.,Das, A.,Rao, D.R.,Hosur, M.V.
Insights into the mechanism of drug resistance: X-ray structure analysis of G48V/C95F tethered HIV-1 protease dimer/saquinavir complex
Biochem.Biophys.Res.Commun., 396:1018-1023, 2010

PubMed Abstract: The mutation G48V in HIV-1 protease is a major resistance mutation against the drug saquinavir. Recently, G48V mutation is found to co-exist with the mutation C95F in AIDS patients treated with saquinavir. We report here the three-dimensional crystal structure of G48V/C95F tethered HIV-1 protease/saquinavir complex. The structure indicates following as the possible causes of drug resistance: (1) loss of direct van der Waals interactions between saquinavir and enzyme residues PHE-53 and PRO-1081, (2) loss of water-mediated hydrogen bonds between the carbonyl oxygen atoms in saquinavir and amide nitrogen atoms of flap residues 50 and 1050, (3) changes in inter-monomer interactions, which could affect the energetics of domain movements associated with inhibitor-binding, and (4) significant reduction in the stability of the mutant dimer. The present structure also provides a rationale for the clinical observation that the resistance mutations C95F/G48V/V82A occur as a cluster in AIDS patients.

PubMed: 20471372
DOI: 10.1016/j.bbrc.2010.05.049

Experimental method

X-RAY DIFFRACTION (2.501 Å)