Binding of topotecan to a nicked DNA oligomer in solution |
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| Authors: | Bocian W Kawecki R Bednarek E Sitkowski J Williamson M P Hansen P E Kozerski L |
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| Institution: | 1. National Medicines Institute, 00‐725 Warszawa, Che?mska 30/34, Poland, Fax: (+48)?22‐8410652;2. Institute of Organic Chemistry, Polish Academy of Sciences, 01‐224 Warszawa, Kasprzaka 44, Poland, Fax: (+48)?22‐6326681;3. Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, UK, Fax: (+44)?114‐222‐2800;4. Department of Life Sciences and Chemistry, Roskilde University, DK‐4000 Roskilde, Denmark, Fax: (+45)‐46743011 |
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| Abstract: | Topotecan (TPT) is in clinical use as an antitumor agent. It acts by binding to the covalent complex formed between nicked DNA and topoisomerase I, and inserts itself into the single-strand nick, thereby inhibiting the religation of the nick and acting as a poison. A crystal structure analysis of the ternary complex has shown how the drug binds (B. L. Staker, K. Hjerrild, M. D. Feese, C. A. Behnke, A. B. Burgin, L. Stewart, Proc. Natl. Acad. Sci. U.S.A., 2002, 99, 15 387-15 392), but has left a number of unanswered questions. Herein, we use NMR spectroscopy and molecular modeling to show that the solution structure of a complex of TPT with nicked natural DNA is similar, but not identical to the crystal conformation, and that other geometries are of very low population. We also show that the lactone form of TPT binds approximately 40 times more strongly than the ring-opened carboxylate. |
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| Keywords: | alkaloids antitumor agents DNA binding molecular dynamics NMR spectroscopy |
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