Sequence-dependent bending of DNA induced by cisplatin: NMR structures of an A.T-rich 14-mer duplex.
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 degrees) 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 degrees), leading to an overall helix bend of 52 +/- 9 degrees. The platinum atom is displaced from the planes of the coordinated G7* and G8* by 0.8 A and 0.3 A, 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 degrees. 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.
Parkinson
J A
JA
Department of Chemistry, University of Edinburgh, UK.
Chen
Y
Y
del Socorro Murdoch
P
P
Guo
Z
Z
Berners-Price
S J
SJ
Brown
T
T
Sadler
P J
PJ
D001483:Base Sequence; D002945:Cisplatin / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D019906:Nuclear Magnetic Resonance, Biomolecular; D009690:Nucleic Acid Conformation
D004247:DNA; D002945:Cisplatin