2.4 angstrom crystal structure of an oxaliplatin 1,2-d(GpG) intrastrand cross-link in a DNA dodecamer duplex

(1R,2R-Diaminocyclohexane)oxalatoplatinum(II) (oxaliplatin) is a third-gene ration platinum anticancer compound that produces the same type of inter- a nd intrastrand DNA cross-links as cisplatin. In combination with 5-fluorour acil, oxaliplatin has been recently approved in Europe, Asia, and Latin Ame rica for the treatment of metastatic colorectal cancer. We present here the crystal structure of an oxaliplatin adduct of a DNA dodecanucleotide duple x having the same sequence as that previously reported for cisplatin (Takah ara, P. M.; Rosenzweig, A. C.; Frederick, C. A.; Lippard, S. J. Nature 1995 , 377, 649-652). Pt-MAD data were used to solve this first X-ray structure of a platinated DNA duplex derived from an active platinum anticancer drug other than cisplatin. The overall geometry and crystal packing of the compl ex, refined to 2.4 Angstrom resolution, are similar to those of the cisplat in structure, despite the fact that the two molecules crystallize in differ ent space groups. The platinum atom of the {Pt(R,R-DACH)}(2+) moiety forms a 1,2-intrastrand cross-link between two adjacent guanosine residues in the sequence 5'-d(CCTCTGGTCTCC), bending the double helix by similar to 30 deg rees toward the major groove. Both end-to-end and end-to-groove packing int eractions occur in the crystal lattice. The latter is positioned in the min or groove opposite the platinum cross-link. A novel feature of the present structure is the presence of a hydrogen bond between the pseudoequatorial N H hydrogen atom of the (R,R)-DACH ligand and the O6 atom of the 3'-G of the platinated d(GpG) lesion. This finding provides structural evidence for th e importance of chirality in mediating the interaction between oxaliplatin and duplex DNA, calibrating previously published models used to explain the reactivity of enantiomerically pure vicinal diamine platinum complexes wit h DNA in solution. It also provides a new kind of chiral recognition betwee n an enantiomerically pure metal complex and the DNA double helix.