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PDBsum entry 3lk9
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Lyase,transferase/DNA
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PDB id
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3lk9
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References listed in PDB file
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Key reference
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Title
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Synthesis and biological evaluation of fluorinated deoxynucleotide analogs based on bis-(Difluoromethylene)triphosphoric acid.
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Authors
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G.K.Surya prakash,
M.Zibinsky,
T.G.Upton,
B.A.Kashemirov,
C.E.Mckenna,
K.Oertell,
M.F.Goodman,
V.K.Batra,
L.C.Pedersen,
W.A.Beard,
D.D.Shock,
S.H.Wilson,
G.A.Olah.
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Ref.
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Proc Natl Acad Sci U S A, 2010,
107,
15693-15698.
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PubMed id
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Abstract
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It is difficult to overestimate the importance of nucleoside triphosphates in
cellular chemistry: They are the building blocks for DNA and RNA and important
sources of energy. Modifications of biologically important organic molecules
with fluorine are of great interest to chemists and biologists because the size
and electronegativity of the fluorine atom can be used to make defined
structural alterations to biologically important molecules. Although the concept
of nonhydrolyzable nucleotides has been around for some time, the progress in
the area of modified triphosphates was limited by the lack of synthetic methods
allowing to access bisCF(2)-substituted nucleotide analogs-one of the most
interesting classes of nonhydrolyzable nucleotides. These compounds have
"correct" polarity and the smallest possible steric perturbation
compared to natural nucleotides. No other known nucleotides have these
advantages, making bisCF(2)-substituted analogs unique. Herein, we report a
concise route for the preparation of hitherto unknown highly acidic and
polybasic bis(difluoromethylene)triphosphoric acid 1 using a
phosphorous(III)/phosphorous(V) interconversion approach. The analog 1 compared
to triphosphoric acid is enzymatically nonhydrolyzable due to substitution of
two bridging oxygen atoms with CF(2) groups, maintaining minimal perturbations
in steric bulkiness and overall polarity of the triphosphate polyanion. The
fluorinated triphosphoric acid 1 was used for the preparation of the
corresponding fluorinated deoxynucleotides (dNTPs). One of these dNTP analogs
(dT) was demonstrated to fit into DNA polymerase beta (DNA pol beta) binding
pocket by obtaining a 2.5 A resolution crystal structure of a ternary complex
with the enzyme. Unexpected dominating effect of triphosphate/Mg(2+) interaction
over Watson-Crick hydrogen bonding was found and discussed.
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