Isohelicity and phasing in drug-DNA sequence recognition: Crystal structure of a tris(benzimidazole)-oligonucleotide complex

The crystal structure is reported of a tris(benzimidazole) analogue of the minor-groove drug Hoechst 33258 bound to the sequence d(CGCAAATTTGCG)(2). The structure has been refined to an R factor of 17.4% at a resolution of 2.2 Angstrom. The ligand covers similar to 7 1/2 base pairs, including the 5'-AAATTT central sequence. This has an exceptionally narrow minor-groove width, together with high propeller twists for individual base pairs. The ligand has a highly twisted structure, with an overall twist of 50 degrees between aromatic rings. All three benzimidazole subunits are in register with the DNA, and there is a symmetric group of six hydrogen bonds between ligand and A . T base-pair edges. By contrast, the ligand does not show an optimal isohelical fit to the DNA. The correct phasing of drug and DNA base pairs is ensured by a number of changes to the DNA such that the central 5'-AAATTT region is slightly unwound relative to the structures of other noncovalent minor-groove drug complexes.