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Nucleic Acids Research 2005 33(17):5622-5632; doi:10.1093/nar/gki869
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Published online 28 September 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Article

Characterization of the bisintercalative DNA binding mode of a bifunctional platinum–acridine agent

Jayati Roy Choudhury and Ulrich Bierbach*

Department of Chemistry, Wake Forest University Winston-Salem, NC 27109-7486, USA

*To whom correspondence should be addressed. Tel: +1 336 758 3507; Fax: +1 336 758 4656; Email: bierbau{at}wfu.edu

Received June 20, 2005. Revised August 23, 2005. Accepted September 9, 2005.

The DNA interactions of PT-BIS(ACRAMTU) ([Pt(en)(ACRAMTU)2](NO3)4; ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea, en = ethylenediamine), a bifunctional platinum–acridine conjugate, have been studied in native and synthetic double-stranded DNAs and model duplexes using various biophysical techniques. These include ethidium-DNA fluorescence quenching and thermal melting experiments, circular dichroism (CD) spectroscopy and plasmid unwinding assays. In addition, the binding mode was studied in a short octamer by NMR spectroscopy in conjunction with molecular modeling. In alternating copolymers, PT-BIS(ACRAMTU) shows a distinct preference for poly(dA-dT)2, which is ~3-fold higher than that of ACRAMTU. In the ligand-oligomer complex, d(GCTATAGC)2·PT-BIS(ACRAMTU) (complex I*), PT-BIS(ACRAMTU) increases the thermal stability of the B-form host duplex by {Delta}Tm > 30 K (CD and UV melting experiments). The agent unwinds pSP73 plasmid DNA by 44(±2)° per bound molecule, indicating bisintercalative binding. A 2-D NMR study unequivocally demonstrates that PT-BIS(ACRAMTU)'s chromophores deeply bisintercalate into the 5'-TA/TA base pair steps in I*, while the platinum linker lies in the minor groove. An AMBER model reflecting the NMR results shows that bracketing of the central AT base pairs in a classical nearest neighbor excluded fashion is feasible. PT-BIS(ACRAMTU) inhibits DNA hydrolysis by BstZ17 I at the enzyme's restriction site, GTA{downarrow}TAC. Possible consequences for other relevant DNA–protein interactions, such as those involved in TATA-box-mediated transcription initiation and the utility of the platinum-intercalator technology for the design of sequence-specific agents are discussed.


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M. Hayashi and Y. Harada
Direct observation of the reversible unwinding of a single DNA molecule caused by the intercalation of ethidium bromide
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