title: Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action.
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.
authors.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.
authors.forename: Dominic
authors.initials: D
authors.lastname: Birth
authors.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.
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: Kao
authors.affiliation: Institute for Biochemistry and Molecular Biology, ZMBZ, BIOSS Centre for Biological Signalling Studies, University of Freiburg, Stefan-Meier-Strasse 17, 79104 Freiburg, Germany.
authors.forename: Carola
authors.initials: C
authors.lastname: Hunte
mesh_terms: D000962:Antimalarials / Q000378:metabolism* / Q000494:pharmacology; D053626:Atovaquone / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D014450:Electron Transport Complex III / Q000378:metabolism*; D051336:Mitochondrial Membranes; D062105:Molecular Docking Simulation; D010963:Plasmodium falciparum / Q000187:drug effects / Q000378:metabolism; D015800:Protozoan Proteins / Q000187:drug effects / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D020539:Sequence Analysis, Protein; D013057:Spectrum Analysis
chemical_list: D000962:Antimalarials; D015800:Protozoan Proteins; D029701:Saccharomyces cerevisiae Proteins; D014450:Electron Transport Complex III; D053626:Atovaquone