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PDBsum entry 5t8h
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Hydrolase/hydrolase inhibitor
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PDB id
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5t8h
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References listed in PDB file
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Key reference
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Title
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Room temperature neutron crystallography of drug resistant HIV-1 protease uncovers limitations of X-Ray structural analysis at 100 k.
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Authors
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O.Gerlits,
D.A.Keen,
M.P.Blakeley,
J.M.Louis,
I.T.Weber,
A.Kovalevsky.
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Ref.
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J Med Chem, 2017,
60,
2018-2025.
[DOI no: ]
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PubMed id
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Abstract
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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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Secondary reference #1
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Title
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Generalized X-Ray and neutron crystallographic analysis: more accurate and complete structures for biological macromolecules.
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Authors
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P.D.Adams,
M.Mustyakimov,
P.V.Afonine,
P.Langan.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2009,
65,
567-573.
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PubMed id
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