title: Insights into the mechanism of drug resistance: X-ray structure analysis of G48V/C95F tethered HIV-1 protease dimer/saquinavir complex.
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.
authors.affiliation: Solid State Physics Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.
authors.forename: Vishal
authors.initials: V
authors.lastname: Prashar
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Bihani
authors.forename: Amit
authors.initials: A
authors.lastname: Das
authors.forename: D R
authors.initials: DR
authors.lastname: Rao
authors.forename: M V
authors.initials: MV
authors.lastname: Hosur
mesh_terms: D019943:Amino Acid Substitution; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral / Q000235:genetics*; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D009154:Mutation; D055503:Protein Multimerization; D019258:Saquinavir / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D019258:Saquinavir