Many antibiotics in clinical use target the bacterial ribosome by interfering with several mechanistic steps of the protein synthesis machinery. However, targeting the human ribosome in the case of protein synthesis deregulations such as in highly proliferating cancer cells has not been much considered up to now. Here we report the first structure of the human 80S ribosome with a eukaryote-specific antibiotic and show its anti-proliferative effect on cancer cell lines. Structural sorting of the cryo electron microscopy data shows that the cycloheximide ligand induces an equilibrium shift of ribosome subpopulations in different states, revealing that the mechanism of action relies on an active release of the tRNA from the exit site. The structure provides unprecedented insights into the detailed interactions in a ligand-binding pocket of the human ribosome that are required for structure-assisted drug design. Furthermore, anti-proliferative dose response in leukemic cells and interference with synthesis of c-myc and mcl-1 short-lived protein markers reveals specificity of a series of antibiotics towards cytosolic rather than mitochondrial ribosomes, establishing the human ribosome as a promising cancer target. In addition, we present a protocol that primarily uses the crystallographic tools for atomic model building and refinement into cryo-EM maps, as exemplified by our recent human ribosome structure.
To cite this abstract:Alexander Myasnikov, Kundhavai Natchiar, Marielle Nebout, Isabelle Isabelle Hazemann, Véronique Imbert, Heena Khatter, Jean-François Peyron, Bruno Klaholz; Structure-function insights reveal the human ribosome as a cancer target for antibiotics. The 16th European Microscopy Congress, Lyon, France. https://emc-proceedings.com/abstract/structure-function-insights-reveal-the-human-ribosome-as-a-cancer-target-for-antibiotics/. Accessed: September 18, 2020
EMC Abstracts - https://emc-proceedings.com/abstract/structure-function-insights-reveal-the-human-ribosome-as-a-cancer-target-for-antibiotics/