Crystal structure of a double-stranded DNA containing a cisplatin interstrand cross-link at 1.63 angstrom resolution: hydration at the platinated site

cis-diamminedichloroplatinum (II) (cisplatin) is a powerful anti-tumor drug whose target is cellular DNA, In the reaction between DNA and cisplatin, c ovalent intrastrand and interstrand cross-links (ICL) are formed. Two solut ion structures of the ICL have been published recently. In both models the double-helix is bent and unwound but with significantly different angle val ues. We solved the crystal structure at 100K of a double-stranded DNA decam er containing a single cisplatin ICL, using the anomalous scattering (MAD) of platinum as a unique source of phase information. We found 47 degrees fo r double-helix bending and 70 degrees for unwinding in agreement with previ ous electrophoretic assays. The crystals are stabilized by intermolecular c ontacts involving two cytosines extruded from the double-helix, one of whic h makes a triplet with a terminal G.C pair. The platinum coordination is ne arly square and the platinum residue is embedded into a cage of nine water molecules linked to the cross-linked guanines, to the two ammine groups, an d to the phosphodiester backbone through other water molecules, This water molecule organization is discussed in relation with the chemical stability of the ICL.