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PDBsum entry 6dil
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Hydrolase/hydrolase inhibitor
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PDB id
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6dil
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References listed in PDB file
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Key reference
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Title
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Drug resistance mutation l76V alters nonpolar interactions at the flap-Core interface of HIV-1 protease.
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Authors
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A.Wong-Sam,
Y.F.Wang,
Y.Zhang,
A.K.Ghosh,
R.W.Harrison,
I.T.Weber.
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Ref.
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ACS Omega, 2018,
3,
12132-12140.
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PubMed id
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Abstract
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Four HIV-1 protease (PR) inhibitors, clinical inhibitors lopinavir and
tipranavir, and two investigational compounds 4 and 5, were
studied for their effect on the structure and activity of PR with drug-resistant
mutation L76V (PRL76V). Compound 5 exhibited the best
Ki value of 1.9 nM for PRL76V, whereas the other
three inhibitors had Ki values of 4.5-7.6 nM, 2-3 orders of
magnitude worse than for wild-type enzymes. Crystal structures showed only minor
differences in interactions of inhibitors with PRL76V compared to
wild-type complexes. The shorter side chain of Val76 in the mutant lost
hydrophobic interactions with Lys45 and Ile47 in the flap, and with Asp30 and
Thr74 in the protein core, consistent with decreased stability. Inhibitors
forming additional polar interactions with the flaps or dimer interface of
PRL76V were unable to compensate for the decrease in internal
hydrophobic contacts. These structures provide insights for inhibitor design.
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