STRUCTURE OF A NONANUCLEOTIDE DUPLEX CROSS-LINKED BY CISPLATIN AT AN APG SEQUENCE

The structure of the second major adduct formed by the antitumor drug cisplatin with DNA, the intrastand cis-Pt(NH3)(2){d(ApG)N7-N7} chelate (AG*), has been investigated using a double-stranded nonanucleotide, d(CTCAG*CCTC)-d(GAGGCTGAG), by means of NMR and molecular modeling. The NMR data allow us to conclude that the oligonucleotide is kinked a t the platinated site towards the major groove in a way similar to tha t observed elsewhere for the GG*-crosslink in d(GCCG*G*ATCGC)-d(GCGAT CCGGC). The main difference concerns the position of the thymine T(15) complementary to the platinated adenine A(4), It remains stacked on its 5'-neighbor C(14), corresponding to the ''model E'' described prev iously, whereas in the GG*-adduct, the cytosine facing the 5'-G* was found to oscillate between the 5'-branch (''model E'') and the 3'-bran ch (''model C'') of the complementary strand. Two ''E-type'' models ar e presented which account for the particular NOE connectivity and for two remarkable upfield NMR signals: those of the H2' proton of the cyt idine C(3) 5' to the AG* chelate, and of the H3 imino proton of T(15) , the base complementary to A(4). The former shift is attributed to s hielding by the destacked A(4) base, whereas the latter is accounted for by a swinging movement of the T(15) base between two positions whe re the imino Watson-Crick hydrogen bond with A(4) remains intact and the amino hydrogen bond is disrupted, or vice versa. Possible implicat ions of the structural difference between the AG and GG adducts of cis platin in the mutagenic properties of the two adducts are discussed.