Cytochrome b mutations that modify the ubiquinol-binding pocket of the cytochrome bc1 complex and confer anti-malarial drug resistance in Saccharomyces cerevisiae.

Jacques J Kessl, Kevin H Ha, Anne K Merritt, Benjamin B Lange, Philip Hill, Brigitte Meunier, Steven R Meshnick, Bernard L Trumpower

The Journal of biological chemistry 2005 Apr 29

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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.

Citation

Jacques J Kessl, Kevin H Ha, Anne K Merritt, Benjamin B Lange, Philip Hill, Brigitte Meunier, Steven R Meshnick, Bernard L Trumpower. Cytochrome b mutations that modify the ubiquinol-binding pocket of the cytochrome bc1 complex and confer anti-malarial drug resistance in Saccharomyces cerevisiae. The Journal of biological chemistry. 2005 Apr 29;280(17):17142-8