Antimalarial drug artemisinin stabilizes PfRACK1 binding to the ribosome

Go, KD; Yan, XF; Wirjanata, G; Ero, R; Pazicky, S; Dziekan, J; Tjia, S; Lescar, J; Bozdech, Z; Gao, YG

Author(s): Go, KD; Yan, XF; Wirjanata, G; Ero, R; Pazicky, S; Dziekan, J; Tjia, S; Lescar, J; Bozdech, Z; Gao, YG;
Details: Publication Year 2025-08-07,Volume 33,Issue #8,Page 1386-1397.e5
Journal Title: Structure
Abstract: Artemisinin and its derivatives represent the core agents in artemisinin combination therapies that are the current frontline treatment for P. falciparum and P. vivax malaria infections. Artemisinins are known to bind a wide array of proteins that disrupt the parasite's cellular physiology. Here, we show that artemisinins' cytotoxic activity involves structural alteration of key P. falciparum macromolecular complexes, including the ribosome, proteasome, and T-complex. The structural analysis revealed that, following artemisinin treatment, a larger population of Pf80S ribosomes binds PfRACK1. Unlike in most eukaryotes, PfRACK1 does not interact with the C-terminal tail of the r-protein uS3 that in Plasmodium is truncated. This likely suggests an evolved role of uS3 in facilitating RACK1-mediated translational regulation, which would potentially benefit the parasite under certain conditions. Stabilization of RACK1 ribosome interaction likely contributes to artemisinins' mode of action.
Publisher: Cell Press
Keywords: *Artemisinins/pharmacology/chemistry; *Plasmodium falciparum/metabolism/drug effects/chemistry; *Ribosomes/metabolism/chemistry/drug effects; *Antimalarials/pharmacology/chemistry; *Protozoan Proteins/metabolism/chemistry; Protein Binding; Receptors for Activated C Kinase; Humans; Models, Molecular; Binding Sites; Ms-cetsa; Plasmodium falciparum; antiplasmodial mode of action and drug resistance; artemisinin; artemisinin combination therapies; malaria; mass spectrometry-cellular thermal shift assay; receptor for activated C kinase 1; structure of RACK1 bound to Plasmodium falciparum 80S
Research Division(s): Infection and Global Health
PubMed ID: 40480224
Publisher's Version: https://doi.org/10.1016/j.str.2025.05.008
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-09-23 11:15:46

Last Modified: 2025-09-23 11:16:09