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Nat Commun. 2016 Sep 26;7:12856. doi: 10.1038/ncomms12856.

Structure-function insights reveal the human ribosome as a cancer target for antibiotics.

Myasnikov AG1,2,3,4, Kundhavai Natchiar S1,2,3,4, Nebout M5,6, Hazemann I1,2,3,4, Imbert V5,6, Khatter H1,2,3,4, Peyron JF5,6, Klaholz BP1,2,3,4.

Author information

1
Centre for Integrative Biology (CBI), Department of Integrated Structural Biology, IGBMC (Institute of Genetics and of Molecular and Cellular Biology), 1 rue Laurent Fries, Illkirch 67404, France.
2
Centre National de la Recherche Scientifique (CNRS) UMR 7104, Illkirch, France.
3
Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Illkirch, France.
4
Université de Strasbourg, Strasbourg, France.
5
INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France.
6
Université de Nice-Sophia Antipolis, UFR Médecine, Faculté de Médecine, Nice, France.

Abstract

Many antibiotics in clinical use target the bacterial ribosome by interfering with 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 investigated at the molecular level up to now. Here we report the structure of the human 80S ribosome with a eukaryote-specific antibiotic and show its anti-proliferative effect on several cancer cell lines. The structure provides 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 leukaemic cells and interference with synthesis of c-myc and mcl-1 short-lived protein markers reveals specificity of a series of eukaryote-specific antibiotics towards cytosolic rather than mitochondrial ribosomes, uncovering the human ribosome as a promising cancer target.

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