Sequence-dependent bending of DNA induced by cisplatin: NMR structures of an A center dot T-rich 14-mer duplex

The NMR solution structure of the A . T rich DNA 14-mer duplex d(ATACATGGTA CATA) . d(TATGTACCATGTAT) is reported. This is compared with the NMR struct ure of the same duplex intrastrand cross-linked at the d(G*pG*) site by cis -{Pt(NH3)(2)}(2+). derived from the anticancer drug cisplatin, The unmodifi ed duplex has B-DNA geometry, but there is a large positive base-pair roll (roll angle 24 +/- 2 degrees) at the T9-A10 step on the 3' side of the cent ral GG site. Platination of the DNA duplex causes the adjacent guanine base s to roll toward one another (roll angle 44 +/- 4 degrees), leading to an o verall helix bend of 52 +/- 9 degrees, The platinum atom is displaced from the planes of the coordinated G7* and G8* by 0.8 Angstrom and 0.3 Angstrom. respectively. The minor groove opposite the platinum lesion is widened and flattened, with geometric parameters similar to those of A-form DNA, The u nwinding of the helix at the platination site is 26 degrees. Platination ca uses the DNA duplex to bend toward the 3'-end (with respect to the G*G* str and), in contrast to G . C-rich structures reported previously, which bend toward the 5'-end, This difference can be attributed to the predisposition of the A . T-rich duplex toward bending in this region. Protein recognition of bent platinated G*G* lesions may therefore exhibit a strong dependence on the local DNA structure.