Double helices forming unusual binding motifs: the case of the natural alkaloids coptisine and chelerythrine

Nucleic acids are highly polymorphic biomolecules: their significant structural variability is not only due to sugar-phosphate backbone flexibility, but even to the ability of purine bases to donate and/or to accept hydrogen-bonding by using different molecular sides. Together with the so-called G-quadruplex structures, abundant in many sequenced genomes, recent evidence of unusual binding motifs containing non-guanine-based quartets and other kinds of mismatches has been reported. Small molecules able to preferentially bind mismatching points, instead of the fully matched DNA stretches, are recognized to have potential as drug candidates or tools for chemical biology in vivo. The two natural isoquinoline alkaloids chelerythrine and coptisine are supposed to be unable to interact through classic intercalative processes with ds-DNAs due to their elongated nature and were selected as probes of unusual binding motifs. The X-ray diffraction analyses of the CGTACG/chelerythrine, CGTACG/coptisine and CGATCG/coptisine adducts actually show chelerythrine and coptisine localized at the junction of adjacent DNA helices, in unusual intercalative binding sites containing G:G homo base mismatches, in which the guanines are hydrogen-bonded through their minor groove faces. In the CGTACG/chelerythrine and CGTACG/coptisine, the intercalation site contains six bases and is defined by two 3'-GpC dinucleotides from different chains and completed by two more guanine residues of the 5'-CpG. Also the CGATCG/coptisine complex evidences the same kind of G:G mismatch, in which two C:G:G:C platforms sandwich the alkaloid. In all the reported crystal structures, the overlapping surface between the ligands and the double stranded non-canonical binding sites, is significantly higher than what is expected for classic intercalative binding.