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PDBsum entry 2aoc
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Hydrolase/hydrolase inhibitor
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PDB id
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2aoc
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References listed in PDB file
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Key reference
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Title
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Molecular basis for substrate recognition and drug resistance from 1.1 to 1.6 angstroms resolution crystal structures of HIV-1 protease mutants with substrate analogs.
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Authors
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Y.Tie,
P.I.Boross,
Y.F.Wang,
L.Gaddis,
F.Liu,
X.Chen,
J.Tozser,
R.W.Harrison,
I.T.Weber.
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Ref.
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FEBS J, 2005,
272,
5265-5277.
[DOI no: ]
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PubMed id
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Abstract
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HIV-1 protease (PR) and two drug-resistant variants--PR with the V82A mutation
(PR(V82A)) and PR with the I84V mutation (PR(I84V))--were studied using reduced
peptide analogs of five natural cleavage sites (CA-p2, p2-NC, p6pol-PR, p1-p6
and NC-p1) to understand the structural and kinetic changes. The common
drug-resistant mutations V82A and I84V alter residues forming the
substrate-binding site. Eight crystal structures were refined at resolutions of
1.10-1.60 A. Differences in the PR-analog interactions depended on the peptide
sequence and were consistent with the relative inhibition. Analog p6(pol)-PR
formed more hydrogen bonds of P2 Asn with PR and fewer van der Waals contacts at
P1' Pro compared with those formed by CA-p2 or p2-NC in PR complexes. The P3 Gly
in p1-p6 provided fewer van der Waals contacts and hydrogen bonds at P2-P3 and
more water-mediated interactions. PR(I84V) showed reduced van der Waals
interactions with inhibitor compared with PR, which was consistent with kinetic
data. The structures suggest that the binding affinity for mutants is modulated
by the conformational flexibility of the substrate analogs. The complexes of
PR(V82A) showed smaller shifts of the main chain atoms of Ala82 relative to PR,
but more movement of the peptide analog, compared to complexes with clinical
inhibitors. PR(V82A) was able to compensate for the loss of interaction with
inhibitor caused by mutation, in agreement with kinetic data, but substrate
analogs have more flexibility than the drugs to accommodate the structural
changes caused by mutation. Hence, these structures help to explain how HIV can
develop drug resistance while retaining the ability of PR to hydrolyze natural
substrates.
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Figure 1.
Fig. 1. Electron density map of HIV-1 protease with the
V82A mutation (PR[V82A])–p2-NC crystal structure. The 2Fo–Fc
map was contoured at a level of 2.2  . Hydrogen
bond interactions are shown with distances in Å. (A)
Residues 78–82. (B) Asp30 interacting with P2' Gln.
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Figure 7.
Fig. 7. Structural variation around the active site. (A)
PR–p1-p6 is shown (colored by atom type) superimposed on
D25N–p1-p6 (1KJF) in green bonds. Distances within 4.0 Å
are shown. (B) PR–UIC-94017 is shown as yellow bonds
superimposed on PR–p1-p6 complex (colored by atom type).
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The above figures are
reprinted
from an Open Access publication published by the Federation of European Biochemical Societies:
FEBS J
(2005,
272,
5265-5277)
copyright 2005.
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