X-ray studies on the interaction of the anticancer agent cis-[Pt(NH3)2cl2] to tRNAphe. A mechanism for the formation of the intrastrand cross-link to adjacent guanines in DNA.

The interaction of the potent anticancer agent cis-[Pt(NH3)2cl2] to phenylalanine tRNA from yeast has been investigated by x-ray crystallography. Two major binding sites were excavated from difference Fourier maps and both showed monodentate binding to guanine bases (G15 and G18) at N7. The expected intrastrand cross-linked complex between adjacent guanines was not observed in tRNA. Although both bases G15 and G18 are in the dihydrouridine loop, they are engaged in tertiary base interactions viz. G15-C48 and G18-psi 56. The high C1- ion concentration in the crystal made the reaction sluggish and was perhaps responsible for the formation of only the monodentate complex. This appears to be the initial complex that is formed during the interaction of the Pt drug with DNA, with a subsequent attack of the drug on the N7 of the 5'-side guanine base to generate the expected intrastrand cross-linked product involving adjacent guanines. The wedge-shaped Pt-GG complex that is formed perturbs not only the local geometry but also produces a kink or bend in the DNA duplex.