title: Cytochrome b mutations that modify the ubiquinol-binding pocket of the cytochrome bc1 complex and confer anti-malarial drug resistance in Saccharomyces cerevisiae.
abstract: Atovaquone is a new anti-malarial agent that specifically targets the cytochrome bc1 complex and inhibits parasite respiration. A growing number of failures of this drug in the treatment of malaria have been genetically linked to point mutations in the mitochondrial cytochrome b gene. To better understand the molecular basis of atovaquone resistance in malaria, we introduced five of these mutations, including the most prevalent variant found in Plasmodium falciparum (Y268S), into the cytochrome b gene of the budding yeast Saccharomyces cerevisiae and thus obtained cytochrome bc1 complexes resistant to inhibition by atovaquone. By modeling the variations in cytochrome b structure and atovaquone binding with the mutated bc1 complexes, we obtained the first quantitative explanation for the molecular basis of atovaquone resistance in malaria parasites.
authors.affiliation: Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755.
authors.forename: Jacques J
authors.initials: JJ
authors.lastname: Kessl
authors.forename: Kevin H
authors.initials: KH
authors.lastname: Ha
authors.forename: Anne K
authors.initials: AK
authors.lastname: Merritt
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Lange
authors.forename: Philip
authors.initials: P
authors.lastname: Hill
authors.forename: Brigitte
authors.initials: B
authors.lastname: Meunier
authors.forename: Steven R
authors.initials: SR
authors.lastname: Meshnick
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Trumpower
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D053626:Atovaquone; D045303:Cytochromes b / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D014450:Electron Transport Complex III / Q000737:chemistry* / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008288:Malaria / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology; D010101:Oxygen Consumption; D010963:Plasmodium falciparum / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013997:Time Factors; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000737:chemistry*
chemical_list: D000962:Antimalarials; D009285:Naphthoquinones; D014451:Ubiquinone; D045303:Cytochromes b; D014450:Electron Transport Complex III; C003741:ubiquinol; D053626:Atovaquone