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

Nat Commun. 2014 Jun 4;5:4029. doi: 10.1038/ncomms5029.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / metabolism*
  • Antimalarials / pharmacology
  • Atovaquone / metabolism*
  • Atovaquone / pharmacology
  • Binding Sites
  • Crystallography, X-Ray
  • Electron Transport Complex III / metabolism*
  • Mitochondrial Membranes
  • Molecular Docking Simulation
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / metabolism
  • Protozoan Proteins / drug effects
  • Protozoan Proteins / metabolism
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Sequence Analysis, Protein
  • Spectrum Analysis

Substances

  • Antimalarials
  • Protozoan Proteins
  • Saccharomyces cerevisiae Proteins
  • Electron Transport Complex III
  • Atovaquone

Associated data

  • PDB/4PD4