Crystal structure of Δ-[Ru(bpy)_2dppz]^(2+) bound to mismatched DNA reveals side-by-side metalloinsertion and intercalation
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)_(2)dppz]^(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.
© 2012 Macmillan Publishers Limited. Received 22 December 2011; Accepted 26 April 2011; Published online 10 June 2012. The authors thank S.C. Virgil for assistance in the separation of enantiomers and D.C. Rees and J.A. Hoy for valuable discussions. The authors are grateful to the National Institutes of Health (NIH GM33309 to J.K.B.) for financial support and the Tobacco-Related Disease Research Program (TRDRP) for a Dissertation Research Award to H.S. The authors also acknowledge the Gordon and Betty Moore Foundation and Sanofi-Aventis Bioengineering Research Program at Caltech for support of the X-ray Facility at Caltech Molecular Observatory. The rotation camera facility at Stanford Synchrotron Radiation Laboratory is supported by the US Department of Energy and the NIH. Author contributions: J.K.B. and H.S. designed the research. H.S. carried out crystallization and solution luminescence experiments. J.T.K. and H.S. solved the crystal structure. H.S. and J.K.B. wrote the manuscript.
Accepted Version - nihms-385191.pdf