NMR Solution Structure of a DNA Dodecamer Duplex Containing a cis-Diammineplatinum(II) d(GpG) Intrastrand Cross-Link, the Major Adduct of the Anticancer Drug Cisplatin

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Abstract
The structure of the DNA duplex dodecamer, d(CCTCTG*G*TCTCC·GGAGACCAGAGG), containing the cisplatin d(GpG) 1,2-intrastrand cross-link at the position denoted by asterisks, was determined in solution by high-resolution 2D NMR spectroscopy and restrained molecular dynamics refinement. The cis-[Pt(NH3)2{d(GpG-N7(1),N7(2))}] lesion causes the adjacent guanine bases to roll toward one another by 49°, leading to an overall helix bend angle of 78°. These features are more exaggerated than those observed in the X-ray crystal structure determined for the same platinated duplex [Takahara et al. (1995) Nature377, 649−652]. A common property of the solution and crystal structures is the widening and flattening of the minor groove opposite the platinum adduct, affording geometric parameters resembling those found in A-form DNA. This deformation is especially noteworthy for the solution structure because its sugar puckers are primarily those of B-form DNA. The unwinding of the helix at the site of platination is 25°. The curvature and shape of the platinated duplex are remarkably similar to those observed in DNA duplexes complexed by the HMG-domain proteins SRY and LEF-1. The structure reveals how cisplatin binding alters DNA in such a manner as to facilitate HMG-domain protein recognition.

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