title: Cryo-EM structure of the Plasmodium falciparum 80S ribosome bound to the anti-protozoan drug emetine.
abstract: Malaria inflicts an enormous burden on global human health. The emergence of parasite resistance to front-line drugs has prompted a renewed focus on the repositioning of clinically approved drugs as potential anti-malarial therapies. Antibiotics that inhibit protein translation are promising candidates for repositioning. We have solved the cryo-EM structure of the cytoplasmic ribosome from the human malaria parasite, Plasmodium falciparum, in complex with emetine at 3.2 Å resolution. Emetine is an anti-protozoan drug used in the treatment of ameobiasis that also displays potent anti-malarial activity. Emetine interacts with the E-site of the ribosomal small subunit and shares a similar binding site with the antibiotic pactamycin, thereby delivering its therapeutic effect by blocking mRNA/tRNA translocation. As the first cryo-EM structure that visualizes an antibiotic bound to any ribosome at atomic resolution, this establishes cryo-EM as a powerful tool for screening and guiding the design of drugs that target parasite translation machinery.
authors.affiliation: Division of Infection and Immunity, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
authors.forename: Wilson
authors.initials: W
authors.lastname: Wong
authors.affiliation: Structural Studies, Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
authors.forename: Xiao-chen
authors.initials: XC
authors.lastname: Bai
authors.affiliation: Structural Studies, Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Brown
authors.affiliation: Structural Studies, Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
authors.forename: Israel S
authors.initials: IS
authors.lastname: Fernandez
authors.affiliation: Electron Microscopy Unit, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Australia.
authors.forename: Eric
authors.initials: E
authors.lastname: Hanssen
authors.affiliation: Division of Infection and Immunity, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
authors.forename: Melanie
authors.initials: M
authors.lastname: Condron
authors.affiliation: Division of Infection and Immunity, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
authors.forename: Yan Hong
authors.initials: YH
authors.lastname: Tan
authors.affiliation: Division of Infection and Immunity, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
authors.forename: Jake
authors.identifier: http://orcid.org/0000-0002-0275-352X
authors.initials: J
authors.lastname: Baum
authors.affiliation: Structural Studies, Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
authors.forename: Sjors H W
authors.initials: SH
authors.lastname: Scheres
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry; D001665:Binding Sites; D020285:Cryoelectron Microscopy; D003593:Cytoplasm / Q000378:metabolism; D015195:Drug Design; D004640:Emetine / Q000737:chemistry*; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D008958:Models, Molecular; D010142:Pactamycin / Q000737:chemistry; D010963:Plasmodium falciparum / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D012269:Ribosomal Proteins / Q000737:chemistry; D012270:Ribosomes / Q000737:chemistry* / Q000648:ultrastructure*
chemical_list: D000962:Antimalarials; D012333:RNA, Messenger; D012269:Ribosomal Proteins; D010142:Pactamycin; D004640:Emetine
keywords: Plasmodium falciparum; biophysics; cryo-EM; drug development; malaria; ribosome; structural biology