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Publication Abstract from PubMed

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 Odelta1 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.

Room Temperature Neutron Crystallography of Drug Resistant HIV-1 Protease Uncovers Limitations of X-ray Structural Analysis at 100 K.,Gerlits O, Keen DA, Blakeley MP, Louis JM, Weber IT, Kovalevsky A J Med Chem. 2017 Feb 28. doi: 10.1021/acs.jmedchem.6b01767. PMID:28195728^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.