Sequence-Dependent Bending of DNA Induced by cisplatin:NMR structures of an A.T-Rich 14-mer duplex

Abstract

The NMR solution structure of the A⋅T rich DNA 14-mer duplex d(ATACATGGTACATA)⋅d(TATGTACCATGTAT) is reported. This is compared with the NMR structure 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 unmodified duplex has B-DNA geometry, but there is a large positive base-pair roll (roll angle 24±2°) at the T9–A10 step on the 3′ side of the central GG site. Platination of the DNA duplex causes the adjacent guanine bases to roll toward one another (roll angle 44±4°), leading to an overall helix bend of 52±9°. The platinum atom is displaced from the planes of the coordinated G7* and G8* by 0.8 Å and 0.3 Å, respectively. The minor groove opposite the platinum lesion is widened and flattened, with geometric parameters similar to those of A-form DNA. The unwinding of the helix at the platination site is 26°. Platination causes the DNA duplex to bend toward the 3′-end (with respect to the G*G* strand), 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.