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PDBsum entry 1mnv
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DNA/antibiotic
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PDB id
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1mnv
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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 actinomycin d bound to the ctg triplet repeat sequences linked to neurological diseases.
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Authors
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M.H.Hou,
H.Robinson,
Y.G.Gao,
A.H.Wang.
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Ref.
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Nucleic Acids Res, 2002,
30,
4910-4917.
[DOI no: ]
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PubMed id
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Abstract
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The potent anticancer drug actinomycin D (ActD) acts by binding to DNA GpC
sequences, thereby interfering with essential biological processes including
replication, transcription and topoisomerase. Certain neurological diseases are
correlated with expansion of (CTG)n trinucleotide sequences, which contain many
contiguous GpC sites separated by a single base pair. In order to characterize
the binding of ActD to CTG triplet repeat sequences, we carried out heat
denaturation and CD analyses, which showed that adjacent GpC sequences flanking
a T:T mismatch are preferred ActD-binding sites, and that ActD binding results
in a conformational transition to A-type structure. The structural basis of the
strong binding of ActD to neighboring GpC sites flanking a T:T mismatch was
provided by the crystal structure of ActD bound to ATGCTGCAT, which contains a
CTG triplet sequence. Binding of two ActD molecules to GCTGC causes a kink in
the DNA helix. In addition, using a synthetic self-priming DNA model,
5'-(CAG)4(CTG)(16)-3', we observed that ActD can trap the cruciform or duplexes
of (CTG)n and interfere with the expansion process of CTG triplet repeats as
shown by gel electrophoretic expansion assay. Our results may provide the
possible biological consequence of ActD bound to CTG triplet repeat sequences.
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