Structural basis of noscapine activation for tubulin binding

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.This work was supported by Ministerio de Ciencia e Innovación PID2019-104545RB-I00 and Fondo de Investigaciones Sanitarias COV20-01007 to JFD; CTQ2016-76263-P to AC; Swiss National Science Foundation (31003A_166608) to MOS; H2020 MSCA-ITN-2019 860070 TUBINTRAIN to AEP and JFD and a donation from Club deportivo Escuela Hungaresa de Pontevedra.Peer reviewe