Inhibition of Eukaryotic Translation by the Antitumor Natural Product Agelastatin A.
Fiche publication
Date publication
mai 2017
Journal
Cell chemical biology
Auteurs
Membres identifiés du Cancéropôle Est :
Dr YUSUPOV Marat, Dr YUSUPOVA Gulnara
Tous les auteurs :
McClary B, Zinshteyn B, Meyer M, Jouanneau M, Pellegrino S, Yusupova G, Schuller A, Reyes JCP, Lu J, Guo Z, Ayinde S, Luo C, Dang Y, Romo D, Yusupov M, Green R, Liu JO
Lien Pubmed
Résumé
Protein synthesis plays an essential role in cell proliferation, differentiation, and survival. Inhibitors of eukaryotic translation have entered the clinic, establishing the translation machinery as a promising target for chemotherapy. A recently discovered, structurally unique marine sponge-derived brominated alkaloid, (-)-agelastatin A (AglA), possesses potent antitumor activity. Its underlying mechanism of action, however, has remained unknown. Using a systematic top-down approach, we show that AglA selectively inhibits protein synthesis. Using a high-throughput chemical footprinting method, we mapped the AglA-binding site to the ribosomal A site. A 3.5 Å crystal structure of the 80S eukaryotic ribosome from S. cerevisiae in complex with AglA was obtained, revealing multiple conformational changes of the nucleotide bases in the ribosome accompanying the binding of AglA. Together, these results have unraveled the mechanism of inhibition of eukaryotic translation by AglA at atomic level, paving the way for future structural modifications to develop AglA analogs into novel anticancer agents.
Mots clés
Alkaloids, metabolism, Antineoplastic Agents, metabolism, Biological Products, metabolism, Dose-Response Relationship, Drug, HeLa Cells, Humans, Molecular Docking Simulation, Oxazolidinones, metabolism, Protein Biosynthesis, drug effects, Protein Conformation, Ribosomes, drug effects
Référence
Cell Chem Biol. 2017 May 18;24(5):605-613.e5