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PDBsum entry 3jpr
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Transferase/DNA
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PDB id
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3jpr
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References listed in PDB file
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Key reference
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Title
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Halogenated beta,Gamma-Methylene- And ethylidene-Dgtp-Dna ternary complexes with DNA polymerase beta: structural evidence for stereospecific binding of the fluoromethylene analogues.
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Authors
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V.K.Batra,
L.C.Pedersen,
W.A.Beard,
S.H.Wilson,
B.A.Kashemirov,
T.G.Upton,
M.F.Goodman,
C.E.Mckenna.
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Ref.
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J Am Chem Soc, 2010,
132,
7617-7625.
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PubMed id
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Abstract
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Beta,gamma-fluoromethylene analogues of nucleotides are considered to be useful
mimics of the natural substrates, but direct structural evidence defining their
active site interactions has not been available, including the influence of the
new chiral center introduced at the CHF carbon, as in
beta,gamma-fluoromethylene-dGTP, which forms an active site complex with DNA
polymerase beta, a repair enzyme that plays an important role in base excision
repair (BER) and oncogenesis. We report X-ray crystallographic results for a
series of beta,gamma-CXY dGTP analogues, where X,Y = H, F, Cl, Br, and/or CH(3).
For all three R/S monofluorinated analogues examined (CHF, 3/4; CCH(3)F, 13/14;
CClF 15/16), a single CXF-diastereomer (3, 13, 16) is observed in the active
site complex, with the CXF fluorine atom at a approximately 3 A (bonding)
distance to a guanidinium N of Arg183. In contrast, for the CHCl, CHBr, and
CHCH(3) analogues, both diasteromers (6/7, 8/9, 10/11) populate the dGTP site in
the enzyme complex about equally. The structures of the bound dichloro (5) and
dimethyl (12) analogue complexes indicate little to no steric effect on the
placement of the bound nucleotide backbone. The results suggest that
introduction of a single fluorine atom at the beta,gamma-bridging carbon atom of
these dNTP analogues enables a new, stereospecific interaction within the
preorganized active site complex that is unique to fluorine. The results also
provide the first diverse structural data set permitting an assessment of how
closely this class of dNTP analogues mimics the conformation of the parent
nucleotide within the active site complex.
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