The mechanism of topoisomerase I poisoning by a camptothecin analog.

Bart L Staker, Kathryn Hjerrild, Michael D Feese, Craig A Behnke, Alex B Burgin, Lance Stewart

Proceedings of the National Academy of Sciences of the United States of America 2002 Nov 26

filter terms:

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.

Citation

Bart L Staker, Kathryn Hjerrild, Michael D Feese, Craig A Behnke, Alex B Burgin, Lance Stewart. The mechanism of topoisomerase I poisoning by a camptothecin analog. Proceedings of the National Academy of Sciences of the United States of America. 2002 Nov 26;99(24):15387-92