Cytochrome b mutations that modify the ubiquinol-binding pocket of the cytochrome bc1 complex and confer anti-malarial drug resistance in Saccharomyces cerevisiae.
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.
Kessl
Jacques J
JJ
Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755.
Ha
Kevin H
KH
Merritt
Anne K
AK
Lange
Benjamin B
BB
Hill
Philip
P
Meunier
Brigitte
B
Meshnick
Steven R
SR
Trumpower
Bernard L
BL
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*
D000962:Antimalarials; D009285:Naphthoquinones; D014451:Ubiquinone; D045303:Cytochromes b; D014450:Electron Transport Complex III; C003741:ubiquinol; D053626:Atovaquone