2. Academic Validation
  3. Antimalarial drug artemisinin stabilizes PfRACK1 binding to the ribosome

Antimalarial drug artemisinin stabilizes PfRACK1 binding to the ribosome

  • Structure. 2025 May 27:S0969-2126(25)00186-8. doi: 10.1016/j.str.2025.05.008.
Ka Diam Go 1,  Xin-Fu Yan 2,  Grennady Wirjanata 1,  Rya Ero 1,  Samuel Pazicky 1,  Jerzy Dziekan 3,  Seth Tjia 1,  Julien Lescar 4,  Zbynek Bozdech 5,  Yong-Gui Gao 6
Affiliations

Affiliations

  • 1 School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
  • 2 School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore; NTU Institute of Structural Biology, Nanyang Technological University, Singapore 636921, Singapore.
  • 3 Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
  • 4 School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore; NTU Institute of Structural Biology, Nanyang Technological University, Singapore 636921, Singapore; Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology Centre, 1 CREATE Way, Singapore 138602, Singapore. Electronic address: julien@ntu.edu.sg.
  • 5 School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore. Electronic address: zbozdech@ntu.edu.sg.
  • 6 School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore; NTU Institute of Structural Biology, Nanyang Technological University, Singapore 636921, Singapore. Electronic address: ygao@ntu.edu.sg.
PMID: 40480224 DOI: 10.1016/j.str.2025.05.008
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.

Keywords

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.

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