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PDBsum entry 1t03
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Transferase/antibody/DNA
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PDB id
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1t03
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Contents |
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558 a.a.
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429 a.a.
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211 a.a.
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225 a.a.
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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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Structures of HIV-1 rt-Dna complexes before and after incorporation of the anti-Aids drug tenofovir.
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Authors
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S.Tuske,
S.G.Sarafianos,
A.D.Clark,
J.Ding,
L.K.Naeger,
K.L.White,
M.D.Miller,
C.S.Gibbs,
P.L.Boyer,
P.Clark,
G.Wang,
B.L.Gaffney,
R.A.Jones,
D.M.Jerina,
S.H.Hughes,
E.Arnold.
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Ref.
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Nat Struct Mol Biol, 2004,
11,
469-474.
[DOI no: ]
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PubMed id
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Abstract
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Tenofovir, also known as PMPA, R-9-(2-(phosphonomethoxypropyl)adenine, is a
nucleotide reverse transcriptase (RT) inhibitor. We have determined the crystal
structures of two related complexes of HIV-1 RT with template primer and
tenofovir: (i) a ternary complex at a resolution of 3.0 A of RT crosslinked to a
dideoxy-terminated DNA with tenofovir-diphosphate bound as the incoming
substrate; and (ii) a RT-DNA complex at a resolution of 3.1 A with tenofovir at
the 3' primer terminus. The tenofovir nucleotide in the tenofovir-terminated
structure seems to adopt multiple conformations. Some nucleoside reverse
transcriptase inhibitors, including 3TC and AZT, have elements ('handles') that
project beyond the corresponding elements on normal dNTPs (the 'substrate
envelope'). HIV-1 RT resistance mechanisms to AZT and 3TC take advantage of
these handles; tenofovir's structure lacks handles that could protrude through
the substrate envelope to cause resistance.
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Figure 1.
Figure 1. Comparison of the chemical structures of tenofovir,
dTMP and the NRTIs 3TCMP and AZTMP. The azido group of AZTMP
and the sulfur of the L-  -oxathialone
ring of 3TCMP protrude through the envelope of normal substrates
and can serve as handles for the development of NRTI resistance.
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Figure 4.
Figure 4. The active site of the RT(P) -tenofovir complex with
tenofovir in two conformations. In one conformation
(tenofovir I), tenofovir stacks with the penultimate primer
residue but does not engage in Watson-Crick base-pairing with
the template dTMP. The dashed lines for the two base pairs
upstream of the 3' terminus are labeled 1 -3 and 1' -3' for the
template and primer strands, respectively. In the second
conformation (tenofovir II), the adenine of tenofovir is flipped
out by ~180° relative to the position of adenine in the first
conformation.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Mol Biol
(2004,
11,
469-474)
copyright 2004.
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