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PDBsum entry 1ac9
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References listed in PDB file
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Key reference
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Title
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Solution structure of a DNA decamer containing the antiviral drug ganciclovir: combined use of nmr, Restrained molecular dynamics, And full relaxation matrix refinement.
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Authors
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M.Foti,
S.Marshalko,
E.Schurter,
S.Kumar,
G.P.Beardsley,
B.I.Schweitzer.
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Ref.
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Biochemistry, 1997,
36,
5336-5345.
[DOI no: ]
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PubMed id
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Abstract
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The nucleoside analog 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (ganciclovir,
DHPG) is an antiviral drug that is used in the treatment of a variety of herpes
viruses in immunocompromised patients and in a gene therapy protocol that has
shown promising activity for the treatment of cancer. To probe the structural
effects of ganciclovir when incorporated into DNA, we determined and compared
the solution structure of a modified ganciclovir-containing decamer duplex
[d(CTG)(ganciclovir)d(ATCCAG)]2 and a control duplex d[(CTGGATCCAG)]2 using
nuclear magnetic resonance techniques. 1H and 31P resonances in both duplexes
were assigned using a combination of 2-D 1H and 31P NMR experiments.
Proton-proton distances determined from NOESY data and dihedral angles
determined from DQF-COSY data were used in restrained molecular dynamics
simulations starting from canonical A- and B-form DNA models. Both the control
and ganciclovir sets of simulations converged to B-type structures. These
structures were subjected to full relaxation matrix refinement to produce final
structures that were in excellent agreement with the observed NOE intensities.
Examination of the final ganciclovir-containing structures reveals that the base
of the ganciclovir residue is hydrogen bonded to its complementary dC and is
stacked in the helix; in fact, the base of ganciclovir exhibits increased
stacking with the 5' base relative to the control. Interestingly, some of the
most significant distortions in the structures occur 3' to the lesion site,
including a noticeable kink in the sugar-phosphate backbone at this position.
Further examination reveals that the backbone conformation, sugar pucker, and
glycosidic torsion angle of the residue 3' to the lesion site all indicate an
A-type conformation at this position. A possible correlation of these structural
findings with results obtained from earlier biochemical studies will be
discussed.
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Headers
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