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Abstract
DNA mismatches represent a novel target in the development of diagnostics and therapeutics for cancer, because deficiencies in DNA mismatch repair are implicated in cancers, and cells that are repair-deficient show a high frequency of mismatches. Metal complexes with bulky intercalating ligands serve as probes for DNA mismatches. Here, we report the high-resolution (0.92 Å) crystal structure of the ruthenium ‘light switch’ complex Δ-[Ru(bpy)2dppz]2+ (bpy = 2,2′-bipyridine and dppz = dipyridophenazine), which is known to show luminescence on binding to duplex DNA, bound to both mismatched and well-matched sites in the oligonucleotide 5′-(dCGGAAATTACCG)2-3′ (underline denotes AA mismatches). Two crystallographically independent views reveal that the complex binds mismatches through metalloinsertion, ejecting both mispaired adenosines. Additional ruthenium complexes are intercalated at well-matched sites, creating an array of complexes in the minor groove stabilized by stacking interactions between bpy ligands and extruded adenosines. This structure attests to the generality of metalloinsertion and metallointercalation as DNA binding modes. A ‘light switch’ ruthenium complex is known to show enhanced luminescence in the presence of DNA mismatches — emerging targets for cancer diagnostics and therapeutics — but the way it interacts with DNA has remained unclear. Now, metalloinsertion into and metallointercalation at the minor groove of the double helix have been unambiguously observed in a high-resolution crystal structure.Cite this article
Song, H., Kaiser, J. & Barton, J. Crystal structure of Δ-[Ru(bpy)2dppz]2+ bound to mismatched DNA reveals side-by-side metalloinsertion and intercalation. Nature Chem 4, 615–620 (2012). https://doi.org/10.1038/nchem.1375 