Structural basis for the inhibition of the eukaryotic ribosome

Nicolas Garreau de Loubresse, Irina Prokhorova, Wolf Holtkamp, Marina V. Rodnina, Gulnara Yusupova and Marat Yusupov ()
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Nicolas Garreau de Loubresse: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, Université de Strasbourg, 67404, Illkirch, France
Irina Prokhorova: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, Université de Strasbourg, 67404, Illkirch, France
Wolf Holtkamp: Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany
Marina V. Rodnina: Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany
Gulnara Yusupova: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, Université de Strasbourg, 67404, Illkirch, France
Marat Yusupov: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, Université de Strasbourg, 67404, Illkirch, France

Nature, 2014, vol. 513, issue 7519, 517-522

Abstract: Abstract The ribosome is a molecular machine responsible for protein synthesis and a major target for small-molecule inhibitors. Compared to the wealth of structural information available on ribosome-targeting antibiotics in bacteria, our understanding of the binding mode of ribosome inhibitors in eukaryotes is currently limited. Here we used X-ray crystallography to determine 16 high-resolution structures of 80S ribosomes from Saccharomyces cerevisiae in complexes with 12 eukaryote-specific and 4 broad-spectrum inhibitors. All inhibitors were found associated with messenger RNA and transfer RNA binding sites. In combination with kinetic experiments, the structures suggest a model for the action of cycloheximide and lactimidomycin, which explains why lactimidomycin, the larger compound, specifically targets the first elongation cycle. The study defines common principles of targeting and resistance, provides insights into translation inhibitor mode of action and reveals the structural determinants responsible for species selectivity which could guide future drug development.

Date: 2014
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DOI: 10.1038/nature13737

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