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

Gerlits, Oksana O.; Keen, David A.; Blakeley, Matthew P.; Louis, John M.; Weber, Irene T.; Kovalevskyi, Andrii Y.

doi:10.1021/acs.jmedchem.6b01767

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

Journal Article · Tue Feb 14 00:00:00 EST 2017 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.6b01767· OSTI ID:1361359

Gerlits, Oksana O. ^[1]; Keen, David A. ^[2]; Blakeley, Matthew P. ^[3]; Louis, John M. ^[4]; Weber, Irene T. ^[5]; Kovalevskyi, Andrii Y. ^[6]

Univ. of Tennessee, Knoxville, TN (United States). Joint Inst. of Biological Sciences
Science and Technology Facilities Council (STFC), Oxford (United Kingdom). Rutherford Appleton Lab., ISIS Neutron Source
Inst. Laue-Langevin (ILL), Grenoble (France)
National Inst. of Health (NIH), Bethesda, MD (United States)
Georgia State Univ., Atlanta, GA (United States)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

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.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1361359

Journal Information:: Journal of Medicinal Chemistry, Vol. 60, Issue 5; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 21 works

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