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 A. The ligand covers approximately 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.
CRC Biomolecular Structure Unit, Institute of Cancer Research, Sutton, Surrey, U.K.
G R
GR
Clark
E J
EJ
Gray
S
S
Neidle
Y H
YH
Li
W
W
Leupin
D001562:Benzimidazoles / Q000737:chemistry* / Q000378:metabolism*; D006690:Bisbenzimidazole / Q000031:analogs & derivatives* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D007364:Intercalating Agents / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism*
D001562:Benzimidazoles; D007364:Intercalating Agents; D009838:Oligodeoxyribonucleotides; D004247:DNA; D006690:Bisbenzimidazole