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Room temperature neutron crystallography of drug resistant HIV-1 protease uncovers limitations of X-ray structural analysis at 100K.

Room temperature neutron crystallography of drug resistant HIV-1 protease uncovers limitations of X-ray structural analysis at 100K.
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Gerlits OO, Keen DA, Blakeley MP, Louis JM, Weber IT, Kovalevsky AY,


Gerlits OO, Keen DA, Blakeley MP, Louis JM, Weber IT, Kovalevsky AY, (click to view)

Gerlits OO, Keen DA, Blakeley MP, Louis JM, Weber IT, Kovalevsky AY,

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Journal of medicinal chemistry 2017 02 14() doi 10.1021/acs.jmedchem.6b01767

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 100K 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 100K.

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