Characterizing the DNA binding modes of a topoisomerasei-poisoning terbenzimidazole: Evidence for both intercalative and minor groove binding properties

Daniel S. Pilch, Zhitao Xu, Qun Sun, Edmond J. Lavoie, Leroy F. Liu, Nicholas E. Geacintov, Kenneth J. Breslauer

研究成果: 雜誌貢獻文章同行評審

23 引文 斯高帕斯(Scopus)

摘要

We have used a broad range of spectroscopic and viscometric techniques to demonstrate that the complexation of a cytotoxic, topoisomerase I-poisoning terbenzimidazole (5PTB) with the poly(dA)•poly(dT) duplex exhibits properties characteristic of both intercalation and minor groove binding. Our results reveal the following features: (i) Optical melting profiles reveal that 5PTB binding enhances the thermal stability of the poly(dA)• poly(dT) duplex; (ii) Fluorescence-detected 5PTB binding to the poly(dA)•poly(dT) duplex reveals four apparent "site sizes," ranging from 1 to 13 base pairs (bp) per bound drug; (iii) Flow linear dichroism data suggest conformational heterogeneity among the poly(dA)•poly(dT)-bound 5PTB molecules, with substantial contributions from drug molecules bound in the minor groove; (iv) Fluorescence resonance energy transfer data reveal properties characteristic of a significant contribution from an intercalative mode of binding; (v) Viscometric, fluorescence quenching, and netropsin competition data are consistent with 5PTB binding to poly(dA)•poly(dT) by "mixed" modes, which are operationally defined as single or multiple binding populations that individually and/or collectively express both intercalative and minor groove binding properties. We comment on a potential correlation between drugs that exhibit such "mixed" mode binding motifs and those that express antineoplastic activity through inhibition of topoisomerase I.

原文英語
頁(從 - 到)115-133
頁數19
期刊Drug Design and Discovery
13
發行號3-4
出版狀態已發佈 - 1996

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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