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標題: The structural basis of actinomycin D–bindinginduces nucleotide flipping out, a sharp bendand a left-handed twist in CGG triplet repeats
摘要: The potent anticancer drug actinomycin D (ActD)functions by intercalating into DNA at GpC sites,thereby interrupting essential biological processesincluding replication and transcription. Certainneurological diseases are correlated with the expansionof (CGG)n trinucleotide sequences, whichcontain many contiguous GpC sites separated by asingle G:G mispair. To characterize the binding ofActD to CGG triplet repeat sequences, the structuralbasis for the strong binding of ActD to neighbouringGpC sites flanking a G:G mismatch has beendetermined based on the crystal structure of ActDbound to ATGCGGCAT, which contains a CGGtriplet sequence. The binding of ActD molecules toGCGGC causes many unexpected conformationalchanges including nucleotide flipping out, a sharpbend and a left-handed twist in the DNA helix via atwo site-binding model. Heat denaturation, circulardichroism and surface plasmon resonance analysesshowed that adjacent GpC sequences flanking aG:G mismatch are preferred ActD-binding sites. Inaddition, ActD was shown to bind the hairpin conformationof (CGG)16 in a pairwise combination andwith greater stability than that of other DNAintercalators. Our results provide evidence of apossible biological consequence of ActD bindingto CGG triplet repeat sequences.
Appears in Collections:基因體暨生物資訊學研究所



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