5UMD

Structure of the Plasmodium falciparum 80S ribosome bound to the antimalarial drug mefloquine

This is a non-PDB format compatible entry.

Summary for 5UMD

• Entry DOI: 10.2210/pdb5umd/pdb
• EMDB information: 8576
• Descriptor: 28S ribosomal RNA, 60S ribosomal protein L7-3, putative, 60S ribosomal protein L13, putative, ... (48 entities in total)
• Functional Keywords: ribosome, protein synthesis, antimalarial
• Biological source: Plasmodium falciparum 3D7; More
• Total number of polymer chains: 45
• Total formula weight: 2136615.67

Authors

Wong, W.,Bai, X.-C.,Brown, A.,Scheres, S.,Baum, J. (deposition date: 2017-01-27, release date: 2017-03-01, Last modification date: 2024-11-13)

Primary citation

Wong, W.,Bai, X.C.,Sleebs, B.E.,Triglia, T.,Brown, A.,Thompson, J.K.,Jackson, K.E.,Hanssen, E.,Marapana, D.S.,Fernandez, I.S.,Ralph, S.A.,Cowman, A.F.,Scheres, S.H.,Baum, J.
Mefloquine targets the Plasmodium falciparum 80S ribosome to inhibit protein synthesis.
Nat Microbiol, 2:17031-17031, 2017

PubMed Abstract: Malaria control is heavily dependent on chemotherapeutic agents for disease prevention and drug treatment. Defining the mechanism of action for licensed drugs, for which no target is characterized, is critical to the development of their second-generation derivatives to improve drug potency towards inhibition of their molecular targets. Mefloquine is a widely used antimalarial without a known mode of action. Here, we demonstrate that mefloquine is a protein synthesis inhibitor. We solved a 3.2 Å cryo-electron microscopy structure of the Plasmodium falciparum 80S ribosome with the (+)-mefloquine enantiomer bound to the ribosome GTPase-associated centre. Mutagenesis of mefloquine-binding residues generates parasites with increased resistance, confirming the parasite-killing mechanism. Furthermore, structure-guided derivatives with an altered piperidine group, predicted to improve binding, show enhanced parasiticidal effect. These data reveal one possible mode of action for mefloquine and demonstrate the vast potential of cryo-electron microscopy to guide the development of mefloquine derivatives to inhibit parasite protein synthesis.

PubMed: 28288098
DOI: 10.1038/nmicrobiol.2017.31

Experimental method

ELECTRON MICROSCOPY (3.2 Å)