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Originally published In Press as doi:10.1074/jbc.M206979200 on October 10, 2002

J. Biol. Chem., Vol. 277, Issue 51, 49743-49749, December 20, 2002
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2.4-Å Crystal Structure of the Asymmetric Platinum Complex {Pt(ammine)(cyclohexylamine)}2+ Bound to a Dodecamer DNA Duplex*

Adam P. SilvermanDagger , Weiming Bu, Seth M. Cohen§, and Stephen J. Lippard

From the Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

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-Å 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 38o and a dihedral angle between platinated guanine bases of ~31o. 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.

* This work was supported by a grant from the National Cancer Institute.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and the structure factors (code 1LU5) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

Dagger Undergraduate Research Opportunities Participant.

§ National Institutes of Health postdoctoral fellow.

To whom correspondence should be addressed. Tel.: 617-253-1892; Fax: 617-258-8150; E-mail: lippard@lippard.mit.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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