The structure of a pseudo intercalated complex between actinomycin and the DNA binding sequence d(GpC)

Actinomycin D (AMD) is used clinically to treat tumours such as Wilms' tumour¹ and gestational choriocarcinoma². It inhibits transcription in most cellular systems^3,4, and binds to DNA, not to RNA^3-5, with a preference for guanine⁶. The study of the crystal structure of a 2:1 complex between deoxyguanosine and AMD demonstrated both stacking and hydrogen-bonding interactions between the drug and the guanine ring⁷. Solution studies^8,9 have indicated that the drug binds preferentially to guanine-pyrimidine sequences, such as d(GpC), and that an intercalated complex forms with both DNA¹⁰ and DNA fragments ¹¹. External binding¹² and intercalation^10,13 models for the structure of the complex between AMD and DNA have been proposed, but until now no crystal strucutre of a complex between AMD and an oligonucleotide has been reported. As the smallest unit of DNA with the potential for forming an intercalated duplex is a self-complementary deoxydinucleoside monophosphate, we undertook the crystallographic analysis of the 2:1 complex between deoxyguanylyl-3′, 5′-deoxycytidine, d(GpC), and AMD. The complex is found to form an unusual pseudo-intercalated structure.