Cryo-EM structure of the Plasmodium falciparum 80S ribosome bound to the anti-protozoan drug emetine

作者：Wilson Wong, Xiao‐chen Bai, Alan Brown, I.S. Fernandez, Eric Hanssen, Melanie Condron, Yan Tan, Jake Baum, Sjors H. W. Scheres · 发表于：eLife · 年份：2014 · DOI：10.7554/elife.03080 · 被引用次数：388 · 研究领域：RNA and protein synthesis mechanisms、Peptidase Inhibition and Analysis、Biochemical and Molecular Research

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.