Structure-function insights reveal the human ribosome as a cancer target for antibiotics.
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.
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.|Centre National de la Recherche Scientifique (CNRS) UMR 7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Illkirch, France.|Université de Strasbourg, Strasbourg, France.
Alexander G
AG
Myasnikov
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.|Centre National de la Recherche Scientifique (CNRS) UMR 7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Illkirch, France.|Université de Strasbourg, Strasbourg, France.
S
S
Kundhavai Natchiar
INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France.|Université de Nice-Sophia Antipolis, UFR Médecine, Faculté de Médecine, Nice, France.
Marielle
M
Nebout
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.|Centre National de la Recherche Scientifique (CNRS) UMR 7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Illkirch, France.|Université de Strasbourg, Strasbourg, France.
Isabelle
I
Hazemann
INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France.|Université de Nice-Sophia Antipolis, UFR Médecine, Faculté de Médecine, Nice, France.
Véronique
V
Imbert
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.|Centre National de la Recherche Scientifique (CNRS) UMR 7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Illkirch, France.|Université de Strasbourg, Strasbourg, France.
Heena
H
Khatter
INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France.|Université de Nice-Sophia Antipolis, UFR Médecine, Faculté de Médecine, Nice, France.
Jean-François
JF
Peyron
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.|Centre National de la Recherche Scientifique (CNRS) UMR 7104, Illkirch, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Illkirch, France.|Université de Strasbourg, Strasbourg, France.
Bruno P
BP
Klaholz
J Struct Biol. 2015 Nov;192(2):216-21
26278980
Mol Cell. 2016 Jan 7;61(1):3-14
26585390
Cancer Cell. 2011 Nov 15;20(5):674-88
22094260
Leukemia. 2008 Mar;22(3):608-19
18046443
Leukemia. 2010 Jan;24(1):13-21
19865108
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
20383002
BMC Struct Biol. 2013 Oct 21;13:25
24144335
J Mol Biol. 2003 Oct 31;333(4):721-45
14568533
Nat Rev Cancer. 2003 Mar;3(3):179-92
12612653
J Struct Biol. 2012 Dec;180(3):519-30
23000701
Acta Crystallogr D Biol Crystallogr. 2012 Apr;68(Pt 4):352-67
22505256
Cancer. 2015 May 15;121(10):1637-44
25586015
Nucleic Acids Res. 2014 Apr;42(6):e49
24452798
Nature. 2015 Apr 30;520(7549):640-5
25901680
Nat Methods. 2013 Jun;10(6):584-90
23644547
Nat Methods. 2014 Jan;11(1):63-5
24213166
Leukemia. 2015 Jun;29(6):1253-66
25482130
J Comput Chem. 2004 Oct;25(13):1605-12
15264254
Nat Rev Cancer. 2010 Apr;10(4):301-9
20332779
Clin Cancer Res. 2014 Apr 1;20(7):1735-40
24501394
J Struct Biol. 1996 Jan-Feb;116(1):17-24
8742718
Acta Crystallogr D Biol Crystallogr. 2015 Mar;71(Pt 3):646-66
25760612
Nature. 2014 Sep 25;513(7519):517-22
25209664
Nat Cell Biol. 2013 Jun;15(6):555-64
23728461
Mol Microbiol. 2006 Mar;59(6):1664-77
16553874
Cancer Res. 1972 Oct;32(10):2089-95
4263527