Integrated structural biology of the native malarial translation machinery and its inhibition by an antimalarial drug

Anton, L; Cheng, W; Haile, MT; Dziekan, JM; Cobb, DW; Zhu, X; Han, L; Li, E; Nair, A; Lee, CL; Wang, H; Ke, H; Zhang, G; Doud, EH; Cowman, AF; Ho, CM

Author(s): Anton, L; Cheng, W; Haile, MT; Dziekan, JM; Cobb, DW; Zhu, X; Han, L; Li, E; Nair, A; Lee, CL; Wang, H; Ke, H; Zhang, G; Doud, EH; Cowman, AF; Ho, CM;
Details: Publication Year 2025-11,Volume 32,Issue #11,Page 2158-2164
Journal Title: Nature Structural & Molecular Biology
Publication Type: Aug 18
Abstract: 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.
Publisher: Springer Nature
Keywords: *Plasmodium falciparum/drug effects/metabolism/ultrastructure/genetics; *Antimalarials/pharmacology; Humans; *Ribosomes/metabolism/ultrastructure/drug effects; Cryoelectron Microscopy; Erythrocytes/parasitology; *Protein Biosynthesis/drug effects; Malaria, Falciparum/parasitology/drug therapy; Protozoan Proteins/metabolism; Electron Microscope Tomography; Models, Molecular
Research Division(s): Infection and Global Health
PubMed ID: 40825879
Publisher's Version: https://doi.org/10.1038/s41594-025-01632-3
Open Access at Publisher's Site: https://doi.org/ 10.1038/s41594-025-01632-3
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-08-29 08:41:17

Last Modified: 2025-12-15 01:28:24