Kessl JJ, et al. (2005) Cytochrome b mutations that modify the ubiquinol-binding pocket of the cytochrome bc1 complex and confer anti-malarial drug resistance in Saccharomyces cerevisiae. J Biol Chem 280(17):17142-8
Abstract: Atovaquone is a new anti-malarial agent that specifically targets the cytochrome bc(1) complex and inhibits parasite respiration. A growing number of failures of this drug in treatment of malaria have been genetically linked to point mutations in the mitochondrial cytochrome b gene. To have a better understanding of the molecular basis of atovaquone resistance in malaria, we have 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 bc(1) complexes resistant to inhibition by atovaquone. By modeling the variations in cytochrome b structure and atovaquone binding with the mutated bc1 complexes we have obtained the first quantitative explanation for the molecular basis of atovaquone resistance in malaria parasites.
|Status: Published||Type: Journal Article||PubMed ID: 15718226|
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