5T8H

Joint X-ray/neutron structure of HIV-1 protease triple mutant (V32I,I47V,V82I) with amprenavir at pH 6.0

Summary for 5T8H

• Entry DOI: 10.2210/pdb5t8h/pdb
• Descriptor: Protease, {3-[(4-AMINO-BENZENESULFONYL)-ISOBUTYL-AMINO]-1-BENZYL-2-HYDROXY-PROPYL}-CARBAMIC ACID TETRAHYDRO-FURAN-3-YL ESTER (3 entities in total)
• Functional Keywords: aspartic protease drug resistant mutant amprenavir, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22015.03

Authors

Kovalevsky, A.Y.,Gerlits, O.O. (deposition date: 2016-09-07, release date: 2017-03-01, Last modification date: 2024-04-03)

Primary citation

Gerlits, O.,Keen, D.A.,Blakeley, M.P.,Louis, J.M.,Weber, I.T.,Kovalevsky, A.
Room Temperature Neutron Crystallography of Drug Resistant HIV-1 Protease Uncovers Limitations of X-ray Structural Analysis at 100 K.
J. Med. Chem., 60:2018-2025, 2017

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.

PubMed: 28195728
DOI: 10.1021/acs.jmedchem.6b01767

Experimental method

NEUTRON DIFFRACTION (2.2 Å)
X-RAY DIFFRACTION (1.85 Å)