Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action

Dominic Birth, Wei-Chun Kao and Carola Hunte ()
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Dominic Birth: Institute for Biochemistry and Molecular Biology, ZMBZ, BIOSS Centre for Biological Signalling Studies, University of Freiburg
Wei-Chun Kao: Institute for Biochemistry and Molecular Biology, ZMBZ, BIOSS Centre for Biological Signalling Studies, University of Freiburg
Carola Hunte: Institute for Biochemistry and Molecular Biology, ZMBZ, BIOSS Centre for Biological Signalling Studies, University of Freiburg

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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-Å 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.

Date: 2014
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DOI: 10.1038/ncomms5029

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