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PDBsum entry 2hs1
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References listed in PDB file
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Key reference
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Title
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Ultra-High resolution crystal structure of HIV-1 protease mutant reveals two binding sites for clinical inhibitor tmc114.
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Authors
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A.Y.Kovalevsky,
F.Liu,
S.Leshchenko,
A.K.Ghosh,
J.M.Louis,
R.W.Harrison,
I.T.Weber.
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Ref.
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J Mol Biol, 2006,
363,
161-173.
[DOI no: ]
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PubMed id
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Abstract
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TMC114 (darunavir) is a promising clinical inhibitor of HIV-1 protease (PR) for
treatment of drug resistant HIV/AIDS. We report the ultra-high 0.84 A resolution
crystal structure of the TMC114 complex with PR containing the drug-resistant
mutation V32I (PR(V32I)), and the 1.22 A resolution structure of a complex with
PR(M46L). These structures show TMC114 bound at two distinct sites, one in the
active-site cavity and the second on the surface of one of the flexible flaps in
the PR dimer. Remarkably, TMC114 binds at these two sites simultaneously in two
diastereomers related by inversion of the sulfonamide nitrogen. Moreover, the
flap site is shaped to accommodate the diastereomer with the S-enantiomeric
nitrogen rather than the one with the R-enantiomeric nitrogen. The existence of
the second binding site and two diastereomers suggest a mechanism for the high
effectiveness of TMC114 on drug-resistant HIV and the potential design of new
inhibitors.
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Figure 2.
Figure 2. Hydrogen bonds between the central OH group of
TMC114 and the catalytic Asp25 and Asp25′. The major
conformation of TMC114 is colored by atom type, and the minor
conformation is green. Interatomic distances are shown in
Å. (a) PR-TMC114 (PDB code 1S6G); the TMC114 conformations
were refined with 55% and 45% occupancies. (b) PR[V32I]-TMC114
and (c) PR[M46L]-TMC114. The 2F[o]–F[c] electron density for
the active site residues Asp25 and Asp25′ is shown with the
contour levels of 2.2σ. The alternate conformations have
occupancies of 60% and 40%.
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Figure 3.
Figure 3. Hydrogen bond, C-H…O and C-H…π interactions
are shown in the active site cavity of PR[V32I] for the major
conformation of TMC114 (a) and the minor conformation (b).
Interactions for the alternate conformations of TMC114 in PR and
PR[M46L] are shown in the Supplementary Material.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2006,
363,
161-173)
copyright 2006.
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