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PDBsum entry 1rt2
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Nucleotidyltransferase
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PDB id
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1rt2
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Contents |
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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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Complexes of HIV-1 reverse transcriptase with inhibitors of the hept series reveal conformational changes relevant to the design of potent non-Nucleoside inhibitors.
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Authors
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A.L.Hopkins,
J.Ren,
R.M.Esnouf,
B.E.Willcox,
E.Y.Jones,
C.Ross,
T.Miyasaka,
R.T.Walker,
H.Tanaka,
D.K.Stammers,
D.I.Stuart.
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Ref.
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J Med Chem, 1996,
39,
1589-1600.
[DOI no: ]
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PubMed id
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Abstract
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Crystal structures of HIV-1 reverse transcriptase (RT) complexed with a range of
chemically diverse non-nucleoside inhibitors (NNIs) have shown a single pocket
in which the inhibitors bind and details of the inhibitor-protein interactions.
To delineate the structural requirements for an effective inhibitor, we have
determined the structures of three closely related NNIs which vary widely in
their potencies. Crystal structures of HIV-1 RT complexed with two very potent
inhibitors, MKC-442 and TNK-651, at 2.55 angstroms resolution complement our
previous analysis of the complex with the less effective inhibitor, HEPT. These
structures reveal conformational changes which correlate with changes in
potency. We suggest that a major determinant of increased potency in the
analogues of HEPT is an improved interaction between residue Tyr181 in the
protein and the 6-benzyl ring of the inhibitors which stabilizes the structure
of the complex. This arises through a conformational switching of the protein
structure triggered by the steric bulk of the 5-substituent of the inhibitor
pyrimidine ring.
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Secondary reference #1
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Title
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Mechanism of inhibition of HIV-1 reverse transcriptase by non-Nucleoside inhibitors.
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Authors
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R.Esnouf,
J.Ren,
C.Ross,
Y.Jones,
D.Stammers,
D.Stuart.
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Ref.
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Nat Struct Biol, 1995,
2,
303-308.
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PubMed id
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Secondary reference #2
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Title
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High resolution structures of HIV-1 rt from four rt-Inhibitor complexes.
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Authors
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J.Ren,
R.Esnouf,
E.Garman,
D.Somers,
C.Ross,
I.Kirby,
J.Keeling,
G.Darby,
Y.Jones,
D.Stuart.
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Ref.
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Nat Struct Biol, 1995,
2,
293-302.
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PubMed id
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Secondary reference #3
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Title
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The structure of HIV-1 reverse transcriptase complexed with 9-Chloro-Tibo: lessons for inhibitor design.
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Authors
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J.Ren,
R.Esnouf,
A.Hopkins,
C.Ross,
Y.Jones,
D.Stammers,
D.Stuart.
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Ref.
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Structure, 1995,
3,
915-926.
[DOI no: ]
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PubMed id
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Figure 1.
Figure 1. The structure of 9-chloro-TIBO (R82913) showing the
numbering of atoms in the ring system and the required
stereospecificity of the 5-methyl substituent. Figure 1. The
structure of 9-chloro-TIBO (R82913) showing the numbering of
atoms in the ring system and the required stereospecificity of
the 5-methyl substituent.
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Figure 5.
Figure 5. Ribbon diagram of the form E RT/Cl-TIBO complex using
colour coding to illustrate the structural variation from the
unliganded form E RT structure. Cl-TIBO is shown as a
space-filling model. The form E RT/Cl-TIBO model was produced by
a nine-domain rigid-body refinement of the form F model on to
the partial data set of form E. Hence, some artifactual
variation can be detected near the domain boundaries (light
blue). Figure 5. Ribbon diagram of the form E RT/Cl-TIBO
complex using colour coding to illustrate the structural
variation from the unliganded form E RT structure. Cl-TIBO is
shown as a space-filling model. The form E RT/Cl-TIBO model was
produced by a nine-domain rigid-body refinement of the form F
model on to the partial data set of form E. Hence, some
artifactual variation can be detected near the domain boundaries
(light blue).
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The above figures are
reproduced from the cited reference
with permission from Cell Press
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Secondary reference #4
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Title
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Crystals of HIV-1 reverse transcriptase diffracting to 2.2 a resolution.
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Authors
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D.K.Stammers,
D.O.Somers,
C.K.Ross,
I.Kirby,
P.H.Ray,
J.E.Wilson,
M.Norman,
J.S.Ren,
R.M.Esnouf,
E.F.Garman.
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Ref.
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J Mol Biol, 1994,
242,
586-588.
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PubMed id
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