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

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  • Dominic Birth

    (Institute for Biochemistry and Molecular Biology, ZMBZ, BIOSS Centre for Biological Signalling Studies, University of Freiburg
    Faculty of Biology, University of Freiburg)

  • Wei-Chun Kao

    (Institute for Biochemistry and Molecular Biology, ZMBZ, BIOSS Centre for Biological Signalling Studies, University of Freiburg
    Faculty of Biology, University of Freiburg)

  • Carola Hunte

    (Institute for Biochemistry and Molecular Biology, ZMBZ, BIOSS Centre for Biological Signalling Studies, University of Freiburg)

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.

Suggested Citation

  • Dominic Birth & Wei-Chun Kao & Carola Hunte, 2014. "Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action," Nature Communications, Nature, vol. 5(1), pages 1-11, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5029
    DOI: 10.1038/ncomms5029
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    1. Daniel Riepl & Ana P. Gamiz-Hernandez & Terezia Kovalova & Sylwia M. Król & Sophie L. Mader & Dan Sjöstrand & Martin Högbom & Peter Brzezinski & Ville R. I. Kaila, 2024. "Long-range charge transfer mechanism of the III2IV2 mycobacterial supercomplex," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Jaishree Tripathi & Michal Stoklasa & Sourav Nayak & Kay En Low & Erica Qian Hui Lee & Quang Huy Duong Tien & Laurent Rénia & Benoit Malleret & Zbynek Bozdech, 2024. "The artemisinin-induced dormant stages of Plasmodium falciparum exhibit hallmarks of cellular quiescence/senescence and drug resilience," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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