Room Temperature Neutron Crystallography of Drug Resistant HIV-1 Protease Uncovers Limitations of X-ray Structural Analysis at 100 K.
Oksana GerlitsDavid A KeenMatthew P BlakeleyJohn M LouisIrene T WeberAndrey Y KovalevskyPublished in: Journal of medicinal chemistry (2017)
HIV-1 protease inhibitors are crucial for treatment of HIV-1/AIDS, but their effectiveness is thwarted by rapid emergence of drug resistance. To better understand binding of clinical inhibitors to resistant HIV-1 protease, we used room-temperature joint X-ray/neutron (XN) crystallography to obtain an atomic-resolution structure of the protease triple mutant (V32I/I47V/V82I) in complex with amprenavir. The XN structure reveals a D+ ion located midway between the inner Oδ1 oxygen atoms of the catalytic aspartic acid residues. Comparison of the current XN structure with our previous XN structure of the wild-type HIV-1 protease-amprenavir complex suggests that the three mutations do not significantly alter the drug-enzyme interactions. This is in contrast to the observations in previous 100 K X-ray structures of these complexes that indicated loss of interactions by the drug with the triple mutant protease. These findings, thus, uncover limitations of structural analysis of drug binding using X-ray structures obtained at 100 K.
Keyphrases
- hiv aids
- antiretroviral therapy
- room temperature
- hiv infected
- hiv positive
- high resolution
- drug resistant
- human immunodeficiency virus
- hiv testing
- wild type
- hepatitis c virus
- men who have sex with men
- dual energy
- multidrug resistant
- electron microscopy
- emergency department
- systematic review
- drug induced
- dna binding
- mass spectrometry
- magnetic resonance imaging
- cystic fibrosis
- transcription factor
- quantum dots