Room Temperature Neutron Crystallography of Drug Resistant HIV-1 Protease Uncovers Limitations of X-ray Structural Analysis at 100 K.
Gerlits, O., Keen, D.A., Blakeley, M.P., Louis, J.M., Weber, I.T., Kovalevsky, A.(2017) J Med Chem 60: 2018-2025
- PubMed: 28195728 
- DOI: https://doi.org/10.1021/acs.jmedchem.6b01767
- Primary Citation of Related Structures:  
5T8H - PubMed Abstract: 
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.
Organizational Affiliation: 
UT/ORNL Joint Institute of Biological Sciences, University of Tennessee , Knoxville, Tennessee 37996, United States.