Download MendeleyStructural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action.
Birth, D., Kao, W.C., Hunte, C.(2014) Nat Commun 5: 4029-4029
- PubMed: 24893593
- DOI: https://doi.org/10.1038/ncomms5029
- Primary Citation of Related Structures:
4PD4 - PubMed Abstract:
Atovaquone, a substituted hydroxynaphthoquinone, is a potent antimalarial drug that acts by inhibiting the parasite's mitochondrial cytochrome bc1 complex (cyt bc1). Mutations in cyt bc1 confer atovaquone resistance. Here we describe the X-ray structure of mitochondrial cyt bc1 from Saccharomyces cerevisiae with atovaquone bound in the catalytic Qo site, at 3.0-? resolution. A polarized H-bond to His181 of the Rieske protein in cyt bc1 traps the ionized hydroxyl group of the drug. Side chains of highly conserved cytochrome b residues establish multiple non-polar interactions with the napththoquinone group, whereas less-conserved residues are in contact with atovaquone's cyclohexyl-chlorophenyl tail. Our structural analysis reveals the molecular basis of atovaquone's broad target spectrum, species-specific efficacies and acquired resistances, and may aid drug development to control the spread of resistant parasites.
Organizational Affiliation:
1] Institute for Biochemistry and Molecular Biology, ZMBZ, BIOSS Centre for Biological Signalling Studies, University of Freiburg, Stefan-Meier-Strasse 17, 79104 Freiburg, Germany [2] Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
