Integrated structural biology of the native malarial translation machinery and its inhibition by an antimalarial drug
Our understanding of cellular events is hampered by the gap between the resolution at which we can observe events inside cells and our ability to replicate physiological conditions in test tubes. Here, we show in Plasmodium falciparum, a non-model organism of high medical importance, that this gap can be bridged by using an integrated structural biology approach to visualize events inside the cell at molecular resolution. We determined eight high-resolution structures of the native malarial ribosome in actively translating states inside P. falciparum-infected human erythrocytes using in situ cryo-electron tomography. Following perturbation with a Plasmodium-specific translation inhibitor, we then observed a decrease in elongation factor-bound ribosomal states and an apparent upregulation of ribosome biogenesis in inhibitor-treated parasites. Our work elucidates new molecular details of the malarial translation elongation cycle and demonstrates direct multiscale visualization of drug-induced phenotypic changes in the structure and localization of individual molecules within the native cellular context.
Authors
- Carolyn L. Lee
- Emma H. Doud (ORCID: https://orcid.org/0000-0003-0049-0073)
- Leonie Anton (ORCID: https://orcid.org/0000-0003-0008-2141)
- David W. Cobb
- Alan F. Cowman (ORCID: https://orcid.org/0000-0001-5145-9004)
- Wenjing Cheng
- Chi-Min Ho (ORCID: https://orcid.org/0000-0003-2132-7320)
- H.X. Wang (ORCID: https://orcid.org/0009-0005-5127-5842)
- Anjali Nair
- Meseret T. Haile (ORCID: https://orcid.org/0000-0002-5512-5260)
- Jerzy M. Dziekan
- Hangjun Ke (ORCID: https://orcid.org/0000-0002-2006-3987)
- Xiyan Zhu
- Guoan Zhang (ORCID: https://orcid.org/0000-0002-9489-6033)
- Leyan Han
- Emerson Li
Institutions
- University of Bern (CH)
- Centers for Disease Control and Prevention (US)
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Cornell University (US)
- Columbia University Irving Medical Center (US)
- The Centers (US)
- Weill Cornell Medicine (US)
- Indiana University – Purdue University Indianapolis (US)
- Drexel University (US)
Publication Details
- Journal
- Nature Structural & Molecular Biology
- Published
- 2025-08-18
- DOI
- https://doi.org/10.1038/s41594-025-01632-3
- Citations
- 5
- Primary Topic
- RNA and protein synthesis mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health
- Weill Cornell Medical College
- University of Colorado Boulder
- School of Medicine, Indiana University
- Medical Research Council
- National Health and Medical Research Council