title: 2.4-A crystal structure of the asymmetric platinum complex [Pt(ammine)(cyclohexylamine)]2+ bound to a dodecamer DNA duplex.
abstract: cis-trans-cis-Ammine(cyclohexylamine)diacetatodichloroplatinum(IV) is an oral analog of the platinum anti-cancer drug cisplatin that is currently in phase III clinical trials. Its active form, [Pt(ammine)(cyclohexylamine)]2+, binds to DNA similarly to cisplatin, forming intra- and interstrand cross-links between adjacent purine bases. Since [Pt(ammine)(cyclohexylamine)]2+ contains two different ligands, it can form two isomeric 1,2-d(GpG) intrastrand cross-links. Here we report the 2.4-A resolution x-ray crystal structure of the major adduct between [Pt(ammine)(cyclohexylamine)]2+ and a DNA dodecamer, using the same sequence as previously reported for crystal structures of cisplatin-DNA (Takahara, P. M., Rosenzweig, A. C., Frederick, C. A., and Lippard, S. J. (1995) Nature 377, 649-652) and oxaliplatin-DNA (Spingler, B., Whittington, D. A., and Lippard, S. J. (2001) Inorg. Chem. 40, 5596-5602). Both duplexes in the asymmetric unit contain 1,2-intrastrand cross-links in which the cyclohexylamine ligand is directed toward the 3'-end of the platinated strand. The chair conformation of the cyclohexyl group is clearly resolved. Platination distorts the duplex, resulting in a global bend angle of about 38(o) and a dihedral angle between platinated guanine bases of approximately 31(o). Both end-to-end and end-to-groove packing interactions occur in the crystal lattice, the latter positioned in the minor groove across from the site of the platinum cross-link. A high degree of homology observed between this structure and the previously reported platinum-DNA structures suggests that these platinum complexes distort the DNA duplex in a very similar manner. These results suggest that differences in activity between these drugs are unlikely to result from gross conformational distortions in DNA structure following platinum intrastrand cross-link formation.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Silverman
authors.forename: Weiming
authors.initials: W
authors.lastname: Bu
authors.forename: Seth M
authors.initials: SM
authors.lastname: Cohen
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lippard
mesh_terms: D002851:Chromatography, High Pressure Liquid; D003432:Cross-Linking Reagents / Q000494:pharmacology; D018360:Crystallography, X-Ray / Q000379:methods; D003514:Cyclohexylamines / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D009841:Oligonucleotides / Q000737:chemistry; D010984:Platinum / Q000737:chemistry*; D011485:Protein Binding; D014965:X-Rays
chemical_list: D003432:Cross-Linking Reagents; D003514:Cyclohexylamines; D008024:Ligands; D009841:Oligonucleotides; D010984:Platinum; D004247:DNA