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Structural analysis of mitochondrial cytochrome bc1 complex with atovaquone bound reveals the molecular basis of antimalarial drug action

Background

The substituted hydroxynaphthoquinone atovaquone is a potent antimalarial drug in use for prevention and therapy, a fundamental part of the ongoing global medicinal strategy to control the disastrous infectious disease. Atovaquone acts via inhibition of the cytochrome bc1 complex (cyt bc1) and related mutations were linked to parasitic drug-resistance.

Materials and methods

The molecular binding mode of atovaquone was analysed by spectroscopy and X-ray crystallography. In addition, a comprehensive cytochrome b sequence analysis was performed to interpret binding interactions of the drug in context of sequence conservation of Qo site amino acid residues [1, 2].

Results

We determined the 3.0-Å resolution X-ray structure of mitochondrial cyt bc1 from Saccharomyces cerevisiae with atovaquone bound in the catalytic Qo site [1]. The drug, which has a pKa of 6.9, forms a polarized H-bond between its ionized hydroxyl group and His181 of the Rieske protein subunit. Multiple non-polar interactions with side chains of cytochrome b residues stabilize hydroxynaphthoquinone and chlorophenyl-cyclohexyl groups. The cytochrome b sequence analysis showed that the majority of the interacting residues are conserved, so that atovaquone binding to the yeast cyt bc1 is likely to resemble the binding to the complexes of the target organisms.

Conclusion

The binding mode provides detailed insights in the molecular basis of broad target spectrum, species-specific efficacies and acquired resistances. This may aid drug development to control the spread of drug-resistant parasites.

References

  1. 1.

    Birth D, Kao WC, Hunte C: Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action. Nat Commun. 2014, 5: 4029-

  2. 2.

    Kao WC, Hunte C: The molecular evolution of the Qo motif. Genome Biol Evol. 2014, 6: 1894-10.1093/gbe/evu147.

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Author information

Correspondence to Dominic Birth.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Keywords

  • Binding Mode
  • Antimalarial Drug
  • Antimalarial Drug Action
  • Site Amino Acid
  • Atovaquone

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