Structural basis of noscapine activation for tubulin binding
| Autor: | Jesús Jiménez-Barbero, Ángeles Canales, Katja Bargsten, María A. Oliva, Michel O. Steinmetz, Andrea E. Prota, Javier Rodríguez-Salarichs, J. Fernando Díaz, Youssef L. Bennani |
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| Přispěvatelé: | Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Swiss National Science Foundation, European Commission, Club Escola Hungaresa de Esgrima de Pontevedra, Oliva, María A. [0000-0002-2215-4639], Prota, Andrea E. [0000-0003-0875-5339], Rodríguez-Salarichs, Javier [0000-0002-2932-0142], Jiménez-Barbero, Jesús [0000-0001-5421-8513], Canales, Ángeles [0000-0003-0542-3080], Steinmetz, Michel O. [0000-0001-6157-3687], Díaz, José Fernando [0000-0003-2743-3319], Oliva, María A., Prota, Andrea E., Rodríguez-Salarichs, Javier, Jiménez-Barbero, Jesús, Canales, Ángeles, Steinmetz, Michel O., Díaz, José Fernando |
| Rok vydání: | 2020 |
| Předmět: |
Steric effects
Noscapine Antineoplastic Agents macromolecular substances Crystallography X-Ray 01 natural sciences Microtubules Anticancer drugs Tubulin binding 03 medical and health sciences chemistry.chemical_compound In vivo Tubulin Drug Discovery medicine Animals Humans Colchicine Cytotoxicity 030304 developmental biology 0303 health sciences Binding Sites biology Alkaloid Tubulin Modulators 0104 chemical sciences 3. Good health Molecular Docking Simulation 010404 medicinal & biomolecular chemistry chemistry Drug Design biology.protein Biophysics Molecular Medicine Protein Binding medicine.drug |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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