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Structural basis for the inhibition of the eukaryotic ribosome

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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)

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.

Suggested Citation

  • Nicolas Garreau de Loubresse & Irina Prokhorova & Wolf Holtkamp & Marina V. Rodnina & Gulnara Yusupova & Marat Yusupov, 2014. "Structural basis for the inhibition of the eukaryotic ribosome," Nature, Nature, vol. 513(7519), pages 517-522, September.
    • Handle: RePEc:nat:nature:v:513:y:2014:i:7519:d:10.1038_nature13737
    DOI: 10.1038/nature13737
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    Cited by:

    1. Anna B. Loveland & Egor Svidritskiy & Denis Susorov & Soojin Lee & Alexander Park & Sarah Zvornicanin & Gabriel Demo & Fen-Biao Gao & Andrei A. Korostelev, 2022. "Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Kewei Qin & Shuhan Yu & Yang Liu & Rongtian Guo & Shiya Guo & Junjie Fei & Yuemeng Wang & Kaiyuan Jia & Zhiqiang Xu & Hu Chen & Fengtian Li & Mengmeng Niu & Mu-Shui Dai & Lunzhi Dai & Yang Cao & Yujun, 2023. "USP36 stabilizes nucleolar Snail1 to promote ribosome biogenesis and cancer cell survival upon ribotoxic stress," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Su, HaiFeng & Lin, JiaFu & Tan, FuRong, 2017. "Progress and perspective of biosynthetic platform for higher-order biofuels," Renewable and Sustainable Energy Reviews, Elsevier, vol. 80(C), pages 801-826.

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