Binding of 9-aminoacridine to bulged-base DNA oligomers from a frame-shift hot spot.
Complexes of 9-aminoacridine and two derivatives with oligomers based on the sequence of a hot spot for frame-shift mutations, 5'dGATGGGGCAG, are investigated by proton NMR and equilibrium dialysis. Competition dialysis experiments show that the drug binds bulge-containing oligomers more strongly than regular duplexes of similar sequence and length, with one apparent strong site. A duplex containing an extra cytidine in a run of C's has the highest affinity for 9-aminoacridine among the sequences tested. An oligomer containing five consecutive G.C pairs shows cooperative drug binding, indicating that G tracts of this length may have an altered helical structure. Complexes of a regular 8-mer and a 9-mer containing a bulged guanosine are examined in detail by two-dimensional NMR techniques. 9-Aminoacridine preferentially binds at TpG sites in the 8-mer but binds primarily at the bulged guanosine in the G-bulge 9-mer. Drug-DNA NOE's in the 8-mer complex are compared with the crystal structure of 9-aminoacridine and 5-iodo-CpG [Sakore et al. (1979) J. Mol. Biol. 135, 763-785]. The NMR data suggest that the drug intercalates across the base pairs of both strands with the amino group projecting into the minor groove.
Woodson
S A
SA
Department of Chemistry, Yale University, New Haven, Connecticut 06511.
Crothers
D M
DM
D000585:Aminacrine / Q000378:metabolism*; D000609:Aminoacridines / Q000378:metabolism*; D001482:Base Composition; D001483:Base Sequence; D004247:DNA / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D009154:Mutation; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000378:metabolism*
D000609:Aminoacridines; D009838:Oligodeoxyribonucleotides; C054505:9-aminoacridine-4-carboxamide; D000585:Aminacrine; D004247:DNA