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The mechanism of topoisomerase I poisoning by a camptothecin analog
Open accessAbstract
We report the x-ray crystal structure of human topoisomerase I covalently joined to double-stranded DNA and bound to the clinically approved anticancer agent Topotecan. Topotecan mimics a DNA base pair and binds at the site of DNA cleavage by intercalating between the upstream (−1) and downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding to the enzyme–substrate complex, Topotecan acts as an uncompetitive inhibitor. The structure can explain several of the known structure–activity relationships of the camptothecin family of anticancer drugs and suggests that there are at least two classes of mutations that can produce a drug-resistant enzyme. The first class includes changes to residues that contribute to direct interactions with the drug, whereas a second class would alter interactions with the DNA and thereby destabilize the drug-binding site.
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Citations
Cited by
Mechanisms of DNA damage, repair, and mutagenesis
Chatterjee, N., & Walker, G. C. (2017) · Environmental and Molecular Mutagenesis · doi:10.1002/em.22087 · Cited by 2,039
“Interestingly, anticancer drugs such as camptothecin and many naturopathic compounds are known to stabilize the TOP1-DNA cleavage complexes [Staker et al., 2002; Han et al., 2008].”
DNA topoisomerases: harnessing and constraining energy to govern chromosome topology
Schoeffler, A. J., & Berger, J. M. (2008) · Quarterly Reviews of Biophysics · doi:10.1017/s003358350800468x · Cited by 490
Topoisomerases as anticancer targets
Delgado, J. L., Hsieh, C.-M., Chan, N.-L., & Hiasa, H. (2018) · Biochemical Journal · doi:10.1042/bcj20160583 · Cited by 481
Camptothecin: current perspectives
Thomas, C. J., Rahier, N. J., & Hecht, S. M. (2004) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2003.11.036 · Cited by 451
New Mechanistic and Functional Insights into DNA Topoisomerases
Chen, S. H., Chan, N.-L., & Hsieh, T.-S. (2013) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061809-100002 · Cited by 369
Metadata
- Authors
- Staker, B. L., Hjerrild, K., Feese, M. D., Behnke, C. A., Burgin, A. B., & Stewart, L.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2002-11-08
- Volume
- 99
- Issue
- 24
- Pages
- 15387-15392
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W1871475547
- Cited by
- 818
- References
- 0
- FWCI
- 10.04
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Staker, B. L., Hjerrild, K., Feese, M. D., Behnke, C. A., Burgin, A. B., & Stewart, L. (2002). The mechanism of topoisomerase I poisoning by a camptothecin analog. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.242259599
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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