DNA-nogalamycin interactions: the crystal structure of d(TGATCA) complexed with nogalamycin

The structure of the self-complementary deoxyoligonucleotide d5'(TGATCA) complexed with nogalamycin, an antitumor anthracycline, has been solved to 1.8 A resolution using X-ray crystallographic methods. The technique of single isomorphous replacement, utilizing the anomalous signal of bromine in derivative data collected at three different wavelengths, Cu K alpha, Mo K alpha, and 0.91 A synchroton radiation, was used. The complex crystallized in space group P4(1)2(1)2 with unit cell dimensions a = 37.2 A and c = 70.1 A. The final structure including 116 water molecules has an overall R factor of 19.5% for the 4767 reflections with F > or = 1 sigma F in the resolution range 10.0-1.8 A. One nogalamycin molecule intercalates between each of the d5'(TpG) steps at both ends of a distorted B DNA double helix. This structure provides the first three-dimensional picture of nogalamycin bound to the triplet sequence d5'(TGA), one of its favorable natural binding sites. The drug exhibits a strict requirement for binding to the 3' side of a pyrimidine and the 5' side of a purine. Nogalamycin has bulky sugar groups at either end of a planar aglycon chromophore; therefore, in order for intercalation to occur, the DNA must either transiently open or flex along the helix axis to allow insertion of the chromophore between the base pairs. Conformational change in nogalamycin is observed in the drug-DNA complex with respect to free nogalamycin. Nogalamycin binding to DNA induces severe deformation to the intercalation site base pairs. In comparison to previously reported anthracycline-DNA structures significant differences in base-pair geometry, drug hydrogen-bonding patterns, and the extent of hydration are observed. The position of the drug in this complex is stabilized by a number of nonbonded forces including van der Waals interactions and extensive direct and solvent-mediated hydrogen bonds to the DNA duplex.