Cryo-EM structure of the Plasmodium falciparum 80S ribosome bound to the anti-protozoan drug emetine

  1. Wilson Wong
  2. Xiao-chen Bai
  3. Alan Brown
  4. Israel S Fernandez
  5. Eric Hanssen
  6. Melanie Condron
  7. Yan Hong Tan
  8. Jake Baum
  9. Sjors HW Scheres  Is a corresponding author
  1. Walter and Eliza Hall Institute of Medical Research, Australia
  2. Medical Research Council Laboratory of Molecular Biology, United Kingdom
  3. Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Australia
  4. Imperial College London, United Kingdom

Abstract

Malaria inflicts an enormous burden on global human health. The emergence of parasite resistance to front-line drugs has prompted a renewed focus on the repositioning of clinically approved drugs as potential anti-malarial therapies. Antibiotics that inhibit protein translation are promising candidates for repositioning. We have solved the cryo-EM structure of the cytoplasmic ribosome from the human malaria parasite, Plasmodium falciparum, in complex with emetine at 3.2 Å resolution. Emetine is an anti-protozoan drug used in the treatment of ameobiasis that also displays potent anti-malarial activity. Emetine interacts with the E-site of the ribosomal small subunit and shares a similar binding site with the antibiotic pactamycin, thereby delivering its therapeutic effect by blocking mRNA/tRNA translocation. As the first cryo-EM structure that visualizes an antibiotic bound to any ribosome at atomic resolution, this establishes cryo-EM as a powerful tool for screening and guiding the design of drugs that target parasite translation machinery.

Article and author information

Author details

  1. Wilson Wong

    Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  2. Xiao-chen Bai

    Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Alan Brown

    Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Israel S Fernandez

    Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Eric Hanssen

    Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Melanie Condron

    Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Yan Hong Tan

    Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Jake Baum

    Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Sjors HW Scheres

    Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom
    For correspondence
    scheres@mrc-lmb.cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Werner Kühlbrandt, Max Planck Institute of Biophysics, Germany

Publication history

  1. Received: April 14, 2014
  2. Accepted: June 6, 2014
  3. Accepted Manuscript published: June 9, 2014 (version 1)
  4. Version of Record published: July 8, 2014 (version 2)

Copyright

© 2014, Wong et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Wilson Wong
  2. Xiao-chen Bai
  3. Alan Brown
  4. Israel S Fernandez
  5. Eric Hanssen
  6. Melanie Condron
  7. Yan Hong Tan
  8. Jake Baum
  9. Sjors HW Scheres
(2014)
Cryo-EM structure of the Plasmodium falciparum 80S ribosome bound to the anti-protozoan drug emetine
eLife 3:e03080.
https://doi.org/10.7554/eLife.03080
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