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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
2.4-Å Crystal Structure of the Asymmetric Platinum Complex
{Pt(ammine)(cyclohexylamine)}2+ Bound to a
Dodecamer DNA Duplex*
Adam P.
Silverman ,
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/).
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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