Cytochrome b mutations that modify the ubiquinol-binding pocket of the cytochrome bc1 complex and confer anti-malarial drug resistance in Saccharomyces cerevisiae |
| |
Authors: | Kessl Jacques J Ha Kevin H Merritt Anne K Lange Benjamin B Hill Philip Meunier Brigitte Meshnick Steven R Trumpower Bernard L |
| |
Institution: | Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755. |
| |
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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|