Structural Basis of Noscapine Activation for Tubulin Binding
María A. Oliva, A.E. Prota, Javier Rodríguez‐Salarichs, Youssef L. Bennani, Jesús Jiménez‐Barbero, Katja Bargsten, Ángeles Canales, Michel O. Steinmetz, J. Fernando Dı́az
Abstract
Noscapine is a natural alkaloid that is used as an antitussive medicine. However, it also acts as a weak anticancer agent in certain in vivo models through a mechanism that is largely unknown. Here, we performed structural studies and show that the cytotoxic agent 7A-O-demethoxy-amino-noscapine (7A-aminonoscapine) binds to the colchicine site of tubulin. We suggest that the 7A-methoxy group of noscapine prevents binding to tubulin due to a steric clash of the compound with the T5-loop of α-tubulin. We further propose that the anticancer activity of noscapine arises from a bioactive metabolite that binds to the colchicine site of tubulin to induce mitotic arrest through a microtubule cytoskeleton-based mechanism.