The Amaryllidaceae Alkaloid Haemanthamine Binds the Eukaryotic Ribosome to Repress Cancer Cell Growth
Date
2018-03
Authors
Pellegrino, Simone
Meyer, Melanie
Zorbas, Christiane
Bouchta, Soumaya A.
Saraf, Kritika
Pelly, Stephen C.
Yusupova, Gulnara
Evidente, Antonio
Mathieu, Veronique
Kornienko, Alexander
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier
Abstract
Alkaloids isolated from the Amaryllidaceae plants have potential as therapeutics for treating human diseases. Haemanthamine has been studied as a novel anticancer agent due to its ability to overcome cancer cell resistance to apoptosis. Biochemical experiments have suggested that hemanthamine targets the ribosome. However, a structural characterization of its mechanism has been missing. Here we present the 3.1 Å resolution X-ray structure of haemanthamine bound to the Saccharomyces cerevisiae 80S ribosome. This structure reveals that haemanthamine targets the A-site cleft on the large ribosomal subunit rearranging rRNA to halt the elongation phase of translation. Furthermore, we provide evidence that haemanthamine and other Amaryllidaceae alkaloids also inhibit specifically ribosome biogenesis, triggering nucleolar stress response and leading to p53 stabilization in cancer cells. Together with a computer-aided interpretation of existing structure-activity relationships of Amaryllidaceae alkaloids congeners, we provide a rationale for designing molecules with enhanced potencies and reduced toxicities.
Description
Keywords
x-ray crystallography, cancer, haemanthamine, nucleolar stress response, p53, peptidyl transferase center, ribosome, ribosome biogenesis, translation elongation, Amaryllidaceae alkaloids, Chemistry and Biochemistry
Citation
Pellegrino, S., Meyer, M., Zorbas, C., Bouchta, S. A., Saraf, K., Pelly, S. C., Yusupova, G., Evidente, A., Mathieu, V., Komienko, A., Lafontaine, D. L. J., Yusupov, M. (2018). The Amaryllidaceae Alkaloid Haemanthamine binds the eukaryotic ribosome to repress cancer cell growth. Structure, 26(3), pp. 416–425.