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Multiscale effects of perturbed translation dynamics inform antimalarial design
Open accessPreprint — published as 10.1038/s41594-025-01632-3 · Paper page
Abstract
Malaria parasites rely heavily on rapid, high fidelity protein synthesis to infect and replicate in human erythrocytes, making translation an attractive target for new antimalarials. Here, we have determined in situ structures of Pf 80S ribosomes in thirteen conformational and compositional states from cryoFIB-milled Plasmodium falciparum -infected human erythrocytes across the stages of asexual intraerythrocytic parasite replication. We observe eight active translation intermediates, enabling us to define the native malarial translation elongation cycle, which surprisingly features a bifurcation at the decoding stage of the cycle that has not previously been described. Examination of perturbations in the distribution of ribosomes among these states in the presence of a malaria-specific translation inhibitor suggests that the inhibitor impedes Pf eEF2 and Pf eEF1α interactions with the ribosome. We integrated our in situ cryoET data with proteomic and ultrastructural data to arrive at a deeper understanding of malarial translation, which will inform development of new therapies.
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Highly accurate protein structure prediction with AlphaFold
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Metadata
- Authors
- Anton, L., Cheng, W., Haile, M. T., Cobb, D. W., Zhu, X., Han, L., Li, E., Nair, A., Lee, C. L., Ke, H., Zhang, G., Doud, E. H., & Ho, C.-M.
- Affiliations
- University of Bern (CH)
- Columbia University Irving Medical Center (US)
- Centers for Disease Control and Prevention (US)
- Drexel University (US)
- Weill Cornell Medicine (US)
- Indiana University Indianapolis (US)
- Corresponding author
- Ho, Chi-Min
- Venue
- Nature Structural & Molecular Biology
- Publisher
- openRxiv
- Published
- 2023-09-06
- Volume
- 32
- Issue
- 11
- Pages
- 2158-2164
- ISSN
- 1545-9985 (ISSN-L)
- PMC
- PMC12618226
- OpenAlex
- W4413290763
- Cited by
- 21
- References
- 1
- Citations by year
- 2026: 13 · 2025: 7 · 2024: 1
- FWCI
- 5.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Nature Structural & Molecular Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Open Access CRIS of the University of Bern
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (200205)
- National Institutes of Health (DP5OD029613)
- Weill Cornell Medical College
- University of Colorado Boulder
- School of Medicine, Indiana University
- Medical Research Council
- National Health and Medical Research Council (1194535)
- National Institute of Allergy and Infectious Diseases (R01AI184855)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
- Keywords
- Plasmodium falciparum, ribosome structure, translation elongation, antimalarial drugs, translation inhibitors, ribosome biogenesis, elongation factors, infected erythrocytes, in situ cryo-electron tomography
- MeSH terms
- Antimalarials, Erythrocytes, Humans, Models, Molecular, Plasmodium falciparum, Ribosomes, Protein Biosynthesis, Protozoan Proteins, Malaria, Falciparum, Cryoelectron Microscopy, Electron Microscope Tomography
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