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PDBsum entry 3qo9
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Transferase, hydrolase/inhibitor
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PDB id
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3qo9
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References listed in PDB file
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Key reference
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Title
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Crystal structure of tert-Butyldimethylsilyl-Spiroaminooxathioledioxide-Thymine (tsao-T) in complex with HIV-1 reverse transcriptase (rt) redefines the elastic limits of the non-Nucleoside inhibitor-Binding pocket.
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Authors
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K.Das,
J.D.Bauman,
A.S.Rim,
C.Dharia,
A.D.Clark,
M.J.Camarasa,
J.Balzarini,
E.Arnold.
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Ref.
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J Med Chem, 2011,
54,
2727-2737.
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PubMed id
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Abstract
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tert-Butyldimethylsilyl-spiroaminooxathioledioxide (TSAO) compounds have an
embedded thymidine-analogue backbone; however, TSAO compounds invoke
non-nucleoside RT inhibitor (NNRTI) resistance mutations. Our crystal structure
of RT:7 (TSAO-T) complex shows that 7 binds inside the NNRTI-binding pocket,
assuming a "dragon" shape, and interacts extensively with almost all
the pocket residues. The structure also explains the structure-activity
relationships and resistance data for TSAO compounds. The binding of 7 causes
hyper-expansion of the pocket and significant rearrangement of RT subdomains.
This nonoptimal complex formation is apparently responsible (1) for the lower
stability of a RT (p66/p51) dimer and (2) for the lower potency of 7 despite of
its extensive interactions with RT. However, the HIV-1 RT:7 structure reveals
novel design features such as (1) interactions with the conserved Tyr183 from
the YMDD-motif and (2) a possible way for an NNRTI to reach the polymerase
active site that may be exploited in designing new NNRTIs.
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Secondary reference #1
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Title
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High-Resolution structures of HIV-1 reverse transcriptase/tmc278 complexes: strategic flexibility explains potency against resistance mutations.
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Authors
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K.Das,
J.D.Bauman,
A.D.Clark,
Y.V.Frenkel,
P.J.Lewi,
A.J.Shatkin,
S.H.Hughes,
E.Arnold.
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Ref.
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Proc Natl Acad Sci U S A, 2008,
105,
1466-1471.
[DOI no: ]
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PubMed id
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Figure 2.
Binding mode of TMC278 to HIV-1 RT. (A) Interactions of
TMC278 (gray) with NNRTI-binding pocket residues (in yellow).
(B) The molecular surface (orange) defines the hydrophobic
tunnel that accommodates the cyanovinyl group of TMC278.
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Figure 4.
Comparison of L100I/K103N mutant RT (orange side
chains)/TMC278 (cyan) structure with the wild-type RT (yellow
side chains)/TMC278 (gray) structures reveals wiggling (A) and
jiggling (B) of TMC278.
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Secondary reference #2
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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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