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PDBsum entry 3oxc
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Hydrolase/hydrolase inhibitor
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PDB id
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3oxc
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References listed in PDB file
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Key reference
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Title
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Atomic resolution crystal structures of HIV-1 protease and mutants V82a and i84V with saquinavir.
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Authors
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Y.Tie,
A.Y.Kovalevsky,
P.Boross,
Y.F.Wang,
A.K.Ghosh,
J.Tozser,
R.W.Harrison,
I.T.Weber.
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Ref.
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Proteins, 2007,
67,
232-242.
[DOI no: ]
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PubMed id
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Abstract
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Saquinavir (SQV), the first antiviral HIV-1 protease (PR) inhibitor approved for
AIDS therapy, has been studied in complexes with PR and the variants PR(I) (84V)
and PR(V) (82A) containing the single mutations I84V and V82A that provide
resistance to all the clinical inhibitors. Atomic resolution crystal structures
(0.97-1.25 A) of the SQV complexes were analyzed in comparison to the protease
complexes with darunavir, a new drug that targets resistant HIV, in order to
understand the molecular basis of drug resistance. PR(I) (84V) and PR(V) (82A)
complexes were obtained in both the space groups P2(1)2(1)2 and P2(1)2(1)2(1),
which provided experimental limits for the conformational flexibility. The SQV
interactions with PR were very similar in the mutant complexes, consistent with
the similar inhibition constants. The mutation from bigger to smaller amino
acids allows more space to accommodate the large group at P1' of SQV, unlike the
reduced interactions observed in darunavir complexes. The residues 79-82 have
adjusted to accommodate the large hydrophobic groups of SQV, suggesting that
these residues are intrinsically flexible and their conformation depends more on
the nature of the inhibitor than on the mutations in this region. This analysis
will assist with development of more effective antiviral inhibitors.
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Figure 1.
Figure 1. The 2F[o] - F[c] electron density map for the crystal
structure of PR[V82A]/SQV. The major conformation is colored by
atom type and the minor one is in magenta. (A) Saquinavir
(contoured at 2.2  level).
(B) Residues 79-82 (contoured at 1.8 level).
(C) Catalytic site (contoured at 1.8 level).
Asp25 and 25  are
shown with the hydroxyl group of SQV.
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Figure 3.
Figure 3. Hydrogen bond interactions between PR and inhibitor.
Hydrogen bond interactions are indicated by dashed lines.
Interactions mediated by water are shown in red. (A) Hydrogen
bond interactions between PR and SQV. (B) Hydrogen bond
interactions between PR and darunavir.
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The above figures are
reprinted
by permission from John Wiley & Sons, Inc.:
Proteins
(2007,
67,
232-242)
copyright 2007.
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Secondary reference #1
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Title
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Authors
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Y.Tie,
A.Y.Kovalevsky,
P.Boross,
Y.-F.Wang,
A.K.Ghosh,
T.Tr.W.Harrison,
I.T.Weber.
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Ref.
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TO BE PUBLISHED ...
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