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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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Roles of conformational and positional adaptability in structure-Based design of tmc125-R165335 (etravirine) and related non-Nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-Type and drug-Resistant HIV-1 variants.
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Authors
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K.Das,
A.D.Clark,
P.J.Lewi,
J.Heeres,
M.R.De jonge,
L.M.Koymans,
H.M.Vinkers,
F.Daeyaert,
D.W.Ludovici,
M.J.Kukla,
B.De corte,
R.W.Kavash,
C.Y.Ho,
H.Ye,
M.A.Lichtenstein,
K.Andries,
R.Pauwels,
M.P.De béthune,
P.L.Boyer,
P.Clark,
S.H.Hughes,
P.A.Janssen,
E.Arnold.
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Ref.
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J Med Chem, 2004,
47,
2550-2560.
[DOI no: ]
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PubMed id
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Abstract
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Anti-AIDS drug candidate and non-nucleoside reverse transcriptase inhibitor
(NNRTI) TMC125-R165335 (etravirine) caused an initial drop in viral load similar
to that observed with a five-drug combination in naïve patients and retains
potency in patients infected with NNRTI-resistant HIV-1 variants. TMC125-R165335
and related anti-AIDS drug candidates can bind the enzyme RT in multiple
conformations and thereby escape the effects of drug-resistance mutations.
Structural studies showed that this inhibitor and other diarylpyrimidine (DAPY)
analogues can adapt to changes in the NNRTI-binding pocket in several ways: (1).
DAPY analogues can bind in at least two conformationally distinct modes; (2).
within a given binding mode, torsional flexibility ("wiggling") of DAPY
analogues permits access to numerous conformational variants; and (3). the
compact design of the DAPY analogues permits significant repositioning and
reorientation (translation and rotation) within the pocket ("jiggling"). Such
adaptations appear to be critical for potency against wild-type and a wide range
of drug-resistant mutant HIV-1 RTs. Exploitation of favorable components of
inhibitor conformational flexibility (such as torsional flexibility about
strategically located chemical bonds) can be a powerful drug design concept,
especially for designing drugs that will be effective against rapidly mutating
targets.
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Secondary reference #1
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Title
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Structure of HIV-1 rt/tibo r 86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors.
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Authors
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J.Ding,
K.Das,
H.Moereels,
L.Koymans,
K.Andries,
P.A.Janssen,
S.H.Hughes,
E.Arnold.
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Ref.
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Nat Struct Biol, 1995,
2,
407-415.
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PubMed id
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Secondary reference #2
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Title
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Structure of HIV-1 reverse transcriptase in a complex with the non-Nucleoside inhibitor alpha-Apa r 95845 at 2.8 a resolution.
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Authors
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J.Ding,
K.Das,
C.Tantillo,
W.Zhang,
A.D.Clark,
S.Jessen,
X.Lu,
Y.Hsiou,
A.Jacobo-Molina,
K.Andries.
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Ref.
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Structure, 1995,
3,
365-379.
[DOI no: ]
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PubMed id
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Figure 2.
Figure 2. (a) Stereoview of difference Fourier maps showing the
fit of α-APA into the electron density. The α-APA coordinates
correspond to the current refined model. The green map is the
difference Fourier map at 3.5 å resolution between the
HIV-1 RT/α-APA R 95845 (dibrominated) complex and the HIV-1
RT/α-APA R 90385 (dichlorinated) complex contoured at a 10σ
level which revealed the positions of two bromine atoms. The
blue map is the mF[o]–F[c] difference Fourier map at 3.0
å resolution calculated from a model before α-APA was
included in the refinement; the phases were computed from the
back-transformation of electron density averaged from three
HIV-1 RT/inhibitor complexes; the map is contoured at 1.5σ. (b)
Stereoview of a portion of a 2mF[o]–F[c] difference Fourier
map at 2.8 å resolution in the region around the
non-nucleoside inhibitor-binding pocket showing the α-APA
inhibitor and some of the nearby amino acid residues. The phases
were computed from the current atomic model (R=0.255) and the
map is contoured at 1.2σ. Figure 2. (a) Stereoview of
difference Fourier maps showing the fit of α-APA into the
electron density. The α-APA coordinates correspond to the
current refined model. The green map is the difference Fourier
map at 3.5 å resolution between the HIV-1 RT/α-APA R
95845 (dibrominated) complex and the HIV-1 RT/α-APA R 90385
(dichlorinated) complex contoured at a 10σ level which revealed
the positions of two bromine atoms. The blue map is the
mF[o]–F[c] difference Fourier map at 3.0 å resolution
calculated from a model before α-APA was included in the
refinement; the phases were computed from the
back-transformation of electron density averaged from three
HIV-1 RT/inhibitor complexes; the map is contoured at 1.5σ. (b)
Stereoview of a portion of a 2mF[o]–F[c] difference Fourier
map at 2.8 å resolution in the region around the
non-nucleoside inhibitor-binding pocket showing the α-APA
inhibitor and some of the nearby amino acid residues. The phases
were computed from the current atomic model (R=0.255) and the
map is contoured at 1.2σ.
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Figure 4.
Figure 4. Close-up of the non-nucleoside inhibitor-binding
pocket in the structure of the HIV-1 RT/α-APA complex looking
through a putative entrance to the pocket, showing interactions
between α-APA and nearby amino acid residues. α-APA is shown
in purple as a ball-and-stick model with carbons purple,
nitrogens cyan, oxygens red and bromines magenta. The β7–β8
portion of p51 has a dashed outline. The side chains are shown
for the amino acid residues that make close contacts with α-APA
(in green), and for the three essential aspartic acid residues
D110, D185 and D186 (in red) at the polymerase active site.
Dashed lines indicate connections between the side chains and
the β-strands. Figure 4. Close-up of the non-nucleoside
inhibitor-binding pocket in the structure of the HIV-1 RT/α-APA
complex looking through a putative entrance to the pocket,
showing interactions between α-APA and nearby amino acid
residues. α-APA is shown in purple as a ball-and-stick model
with carbons purple, nitrogens cyan, oxygens red and bromines
magenta. The β7–β8 portion of p51 has a dashed outline. The
side chains are shown for the amino acid residues that make
close contacts with α-APA (in green), and for the three
essential aspartic acid residues D110, D185 and D186 (in red) at
the polymerase active site. Dashed lines indicate connections
between the side chains and the β-strands.
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The above figures are
reproduced from the cited reference
with permission from Cell Press
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Secondary reference #3
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Title
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Crystal structures of 8-Cl and 9-Cl tibo complexed with wild-Type HIV-1 rt and 8-Cl tibo complexed with the tyr181cys HIV-1 rt drug-Resistant mutant.
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Authors
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K.Das,
J.Ding,
Y.Hsiou,
A.D.Clark,
H.Moereels,
L.Koymans,
K.Andries,
R.Pauwels,
P.A.Janssen,
P.L.Boyer,
P.Clark,
R.H.Smith,
M.B.Kroeger smith,
C.J.Michejda,
S.H.Hughes,
E.Arnold.
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Ref.
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J Mol Biol, 1996,
264,
1085-1100.
[DOI no: ]
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PubMed id
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Figure 1.
Figure 1. Chemical structures
with the numbering scheme used
and distances (E3.6 Å ) between
atoms of the TIBO inhibitor and of
the amino acid residues of the
NNIBP for: (a) 8-Cl TIBO (R86183,
tivirapine) complexed with wild-
type HIV-1 RT; (b) 8-Cl TIBO
complexed with Tyr181Cys mutant
HIV-1 RT; and (c) 9-Cl TIBO
(R82913) complexed with wild-type
HIV-1 RT. An NNIBP residue is
shown only if atoms of that residue
are E3.6 Å from an inhibitor atom
with the exception of Cys181 in (b).
The wings I and II portions of the
inhibitors in the butterfly-like anal-
ogy for NNRTIs (Ding et al., 1995a)
are indicated here and in sub-
sequent Figures by Roman nu-
merals I and II. The dotted line in (a)
indicates the subdivision of atoms
between wings I and II.
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Figure 5.
Figure 5. A stereoview of the superposition (based on the C
a
atoms of the b6-b10-b9 sheet) of the HIV-1 RT/DNA/Fab
complex structure (in gray) (Jacobo-Molina et al., 1993) on the HIV-1 RT/9-Cl TIBO complex structure (in cyan) in the
regions near the NNIBP and the polymerase active site showing the disposition of the b12-b13-b14 sheet containing
the primer grip. Bound 9-Cl TIBO in the HIV-1 RT/9-Cl TIBO complex is shown in gold and the two 3'-terminal
nucleotides 17 and 18 of the primer strand in the HIV-1 RT/DNA/Fab complex are shown with a yellow ball-and-stick
model. The broken line represents interactions between the primer grip and the primer terminal phosphate in the HIV-1
RT/DNA/Fab complex and the arrow indicates the movement of the primer grip that accompanies NNRTI binding.
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The above figures are
reproduced from the cited reference
with permission from Elsevier
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Secondary reference #4
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Title
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Structure and functional implications of the polymerase active site region in a complex of HIV-1 rt with a double-Stranded DNA template-Primer and an antibody FAB fragment at 2.8 a resolution.
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Authors
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J.Ding,
K.Das,
Y.Hsiou,
S.G.Sarafianos,
A.D.Clark,
A.Jacobo-Molina,
C.Tantillo,
S.H.Hughes,
E.Arnold.
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Ref.
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J Mol Biol, 1998,
284,
1095-1111.
[DOI no: ]
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PubMed id
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Figure 1.
Figure 1. Ribbon [Carson 1987] diagram showing the overall
structure of the HIV-1 RT/dsDNA/Fab28 complex. The subdomains of
the p66 and p51 subunits of HIV-1 RT are colored as follows:
fingers, blue; palm, red; thumb, green; connection, yellow; and
RNase H, orange. The bound dsDNA is shown with the template
strand as a dark gray ribbon and the primer strand as a light
gray ribbon; base-pairs are represented by bars. The monoclonal
antibody fragment Fab28 is shown with the light chain in light
gray and the heavy chain in dark gray.
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Figure 3.
Figure 3. (a) Structure of the polymerase active site region
of HIV-1 RT including the primer grip. Secondary structural
elements of the p66 palm subdomain are shown as red ribbons. The
three catalytically essential aspartic acid residues (Asp110,
Asp185, and Asp186) are shown with cyan side-chains. Tyr183 and
Met184, which form part of the conserved YMDD motif, are shown
with gold side-chains. Amino acid residues at the primer grip
are shown in green. The dsDNA is shown with the template strand
in dark gray and the primer strand in light gray. (b) A
schematic diagram showing interactions between the 3′-terminal
nucleotide of the primer strand (Pri1) and amino acid residues
at the polymerase active site, with selected distances given in
Å. Hydrogen-bonding interactions between the side-chain
O^δ1 atom of Asp185 and the 3′-OH of Pri1, and between the
amide nitrogen atom of Met230 of the primer grip and the
phosphate oxygen atom of Pri1 are indicated by heavy lines.
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The above figures are
reproduced from the cited reference
with permission from Elsevier
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Secondary reference #5
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Title
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Evolution of anti-Hiv drug candidates. Part 3: diarylpyrimidine (dapy) analogues.
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Authors
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D.W.Ludovici,
B.L.De corte,
M.J.Kukla,
H.Ye,
C.Y.Ho,
M.A.Lichtenstein,
R.W.Kavash,
K.Andries,
M.P.De béthune,
H.Azijn,
R.Pauwels,
P.J.Lewi,
J.Heeres,
L.M.Koymans,
M.R.De jonge,
K.J.Van aken,
F.F.Daeyaert,
K.Das,
E.Arnold,
P.A.Janssen.
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Ref.
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Bioorg Med Chem Lett, 2001,
11,
2235-2239.
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PubMed id
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