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PDBsum entry 1hqu
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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The lys103asn mutation of HIV-1 rt: a novel mechanism of drug resistance.
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Authors
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Y.Hsiou,
J.Ding,
K.Das,
A.D.Clark,
P.L.Boyer,
P.Lewi,
P.A.Janssen,
J.P.Kleim,
M.Rösner,
S.H.Hughes,
E.Arnold.
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Ref.
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J Mol Biol, 2001,
309,
437-445.
[DOI no: ]
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PubMed id
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Abstract
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Inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT) are
widely used in the treatment of HIV infection. Loviride (an alpha-APA
derivative) and HBY 097 (a quinoxaline derivative) are two potent non-nucleoside
RT inhibitors (NNRTIs) that have been used in human clinical trials. A major
problem for existing anti-retroviral therapy is the emergence of drug-resistant
mutants with reduced susceptibility to the inhibitors. Amino acid residue 103 in
the p66 subunit of HIV-1 RT is located near a putative entrance to a hydrophobic
pocket that binds NNRTIs. Substitution of asparagine for lysine at position 103
of HIV-1 RT is associated with the development of resistance to NNRTIs; this
mutation contributes to clinical failure of treatments employing NNRTIs. We have
determined the structures of the unliganded form of the Lys103Asn mutant HIV-1
RT and in complexes with loviride and HBY 097. The structures of wild-type and
Lys103Asn mutant HIV-1 RT in complexes with NNRTIs are quite similar overall as
well as in the vicinity of the bound NNRTIs. Comparison of unliganded wild-type
and Lys103Asn mutant HIV-1 RT structures reveals a network of hydrogen bonds in
the Lys103Asn mutant that is not present in the wild-type enzyme. Hydrogen bonds
in the unliganded Lys103Asn mutant but not in wild-type HIV-1 RT are observed
between (1) the side-chains of Asn103 and Tyr188 and (2) well-ordered water
molecules in the pocket and nearby pocket residues. The structural differences
between unliganded wild-type and Lys103Asn mutant HIV-1 RT may correspond to
stabilization of the closed-pocket form of the enzyme, which could interfere
with the ability of inhibitors to bind to the enzyme. These results are
consistent with kinetic data indicating that NNRTIs bind more slowly to
Lys103Asn mutant than to wild-type HIV-1 RT. This novel drug-resistance
mechanism explains the broad cross-resistance of Lys103Asn mutant HIV-1 RT to
different classes of NNRTIs. Design of NNRTIs that make favorable interactions
with the Asn103 side-chain should be relatively effective against the Lys103Asn
drug-resistant mutant.
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Figure 3.
Figure 3. Stereoview of a SIGMAA weighted 2mFo
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DFc difference Fourier map showing the electron density in
the NNIBP region of p66 in the unliganded Lys103Asn mutant HIV-1 RT structure. The phases were computed from
the final model at 2.7 Å resolution and the map was contoured at 2s. Selected hydrogen-bonding interactions are
indicated with broken lines.
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Figure 4.
Figure 4. Energy diagram for the binding of an
NNRTI to wild-type and Lys103Asn mutant RT. The
Lys103Asn mutant RT with the additional hydrogen
bonding network in the NNIBP region is assumed to be
more stable than wild-type HIV-1 RT. The relative stab-
ility of wild-type and Lys103Asn mutant HIV-1 RT com-
plexes with NNRTIs will depend on the inhibitor.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2001,
309,
437-445)
copyright 2001.
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Secondary reference #1
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Title
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Structures of tyr188leu mutant and wild-Type HIV-1 reverse transcriptase complexed with the non-Nucleoside inhibitor hby 097: inhibitor flexibility is a useful design feature for reducing drug resistance.
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Authors
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Y.Hsiou,
K.Das,
J.Ding,
A.D.Clark,
J.P.Kleim,
M.Rösner,
I.Winkler,
G.Riess,
S.H.Hughes,
E.Arnold.
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Ref.
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J Mol Biol, 1998,
284,
313-323.
[DOI no: ]
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PubMed id
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Figure 1.
Figure 1. Diagram of HBY 097 (a quinoxaline derivative)
contacts with protein residues around the NNIBP in both (a)
wild-type HIV-1 RT/HBY 097 and (b) Tyr188Leu mutant HIV-1 RT/HBY
097 complexes. Distances (  slant
3.6 Å) between protein and inhibitor atoms are indicated.
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Figure 4.
Figure 4. (a) Stereoview of a difference Fourier m(F[obs] -
F[calc]) map showing the electron density of HBY 097 in the
wild-type HIV-1 RT/HBY 097 complex. The map is calculated at 3.1
Å resolution with 2s contours (in magenta). The phases
were computed from the protein model prior to inclusion of the
inhibitor. The green density corresponds to the difference
Fourier map (3.7 Å resolution) between HBY 097 and S-0483
complexed with wild-type HIV-1 RT (bromine in S-0483 replaces
the methoxy group of HBY 097), contoured at the 5s level,
showing the position of the bromine atom and confirming the
orientation and placement of the inhibitor. Difference Fourier
2mF[obs] - F[calc] map at 3.3 Å resolution, contoured at
1.2s, (b) of the Tyr188Leu mutant HIV-1 RT/HBY 097 complex at
the NNIBP region in p66 showing the absence of any density for
the side-chain of Leu188; clear density for HBY 097 is seen in
the binding pocket; and of a (c) similar region in the p51
subunit, showing clear electron density for the side-chain at
Leu188.
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The above figures are
reproduced from the cited reference
with permission from Elsevier
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