The Amaryllidaceae Alkaloid Haemanthamine Binds the Eukaryotic Ribosome to Repress Cancer Cell Growth.

Fiche publication


Date publication

mars 2018

Journal

Structure (London, England : 1993)

Auteurs

Membres identifiés du Cancéropôle Est :
Dr YUSUPOV Marat, Dr YUSUPOVA Gulnara


Tous les auteurs :
Pellegrino S, Meyer M, Zorbas C, Bouchta SA, Saraf K, Pelly SC, Yusupova G, Evidente A, Mathieu V, Kornienko A, Lafontaine DLJ, Yusupov M

Résumé

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.

Mots clés

Amaryllidaceae alkaloids, X-ray crystallography, cancer, haemanthamine, nucleolar stress response, p53, peptidyl transferase center, ribosome, ribosome biogenesis, translation elongation

Référence

Structure. 2018 Mar 6;26(3):416-425.e4