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

Alexander G. Myasnikov, S. Kundhavai Natchiar, Marielle Nebout, Isabelle Hazemann, Véronique Imbert, Heena Khatter, Jean-François Peyron () and Bruno P. Klaholz ()
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Alexander G. Myasnikov: Centre for Integrative Biology (CBI), IGBMC (Institute of Genetics and of Molecular and Cellular Biology)
S. Kundhavai Natchiar: Centre for Integrative Biology (CBI), IGBMC (Institute of Genetics and of Molecular and Cellular Biology)
Marielle Nebout: INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M)
Isabelle Hazemann: Centre for Integrative Biology (CBI), IGBMC (Institute of Genetics and of Molecular and Cellular Biology)
Véronique Imbert: INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M)
Heena Khatter: Centre for Integrative Biology (CBI), IGBMC (Institute of Genetics and of Molecular and Cellular Biology)
Jean-François Peyron: INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M)
Bruno P. Klaholz: Centre for Integrative Biology (CBI), IGBMC (Institute of Genetics and of Molecular and Cellular Biology)

Nature Communications, 2016, vol. 7, issue 1, 1-8

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12856

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