The potent anticancer drug actinomycin D (ActD) functions by intercalating into DNA at GpC sites, thereby interrupting essential biological processes including replication and transcription. Certain neurological diseases are correlated with the expansion of (CGG)n trinucleotide sequences, which contain many contiguous GpC sites separated by a single G:G mispair. To characterize the binding of ActD to CGG triplet repeat sequences, the structural basis for the strong binding of ActD to neighbouring GpC sites flanking a G:G mismatch has been determined based on the crystal structure of ActD bound to ATGCGGCAT, which contains a CGG triplet sequence. The binding of ActD molecules to GCGGC causes many unexpected conformational changes including nucleotide flipping out, a sharp bend and a left-handed twist in the DNA helix via a two site-binding model. Heat denaturation, circular dichroism and surface plasmon resonance analyses showed that adjacent GpC sequences flanking a G:G mismatch are preferred ActD-binding sites. In addition, ActD was shown to bind the hairpin conformation of (CGG)16 in a pairwise combination and with greater stability than that of other DNA intercalators. Our results provide evidence of a possible biological consequence of ActD binding to CGG triplet repeat sequences.

Small-molecule compounds targeting trinucleotide repeats in DNA have considerable potential as therapeutic or diagnostic agents against many neurological diseases. Ni (Chro) (Chro=chromomycin A3) binds specifically to the minor groove of (CCG) repeats in duplex DNA, with unique fluorescence features that may serve as a probe for disease detection. Crystallographic studies revealed that the specificity originates from the large-scale spatial rearrangement of the DNA structure, including extrusion of consecutive bases and backbone distortions, with a sharp bending of the duplex accompanied by conformational changes in the Ni chelate itself. The DNA deformation of CCG repeats upon binding forms a GGCC tetranucleotide tract, which is recognized by Ni (Chro) . The extruded cytosine and last guanine nucleotides form water-mediated hydrogen bonds, which aid in ligand recognition. The recognition can be accounted for by the classic induced-fit paradigm.

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Small-molecule compounds targeting trinucleotide repeats in DNAh ave considerable potential as therapeutic or diagnostic agents against many neurological diseases.N i II -(Chro) 2 (Chro = chromomycin A3) binds specifically to the minor grooveof(CCG) n repeats in duplex DNA, with unique fluorescence features that mays erve as ap robe for disease detection. Crystallographic studies revealed that the specificity originates from the large-scale spatial rearrangement of the DNAs tructure,i ncluding extrusion of consecutive bases and backbone distortions,w ith as harp bending of the duplex accompanied by conformational changes in the Ni II chelate itself.T he DNAd eformation of CCG repeats upon binding forms aG GCC tetranucleotide tract, which is recognized by Ni II (Chro) 2 .T he extruded cytosine and last guanine nucleotides form water-mediated hydrogen bonds,whichaid in ligand recognition. The recognition can be accounted for by the classic induced-fit paradigm.

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