Abstract
Artemisinins are the most important class of antimalarial drugs. They specifically inhibit PfATP6, a SERCA-type ATPase of Plasmodium falciparum. Here we show that a single amino acid in transmembrane segment 3 of SERCAs can determine susceptibility to artemisinin. An L263E replacement of a malarial by a mammalian residue abolishes inhibition by artemisinins. Introducing residues found in other Plasmodium spp. also modulates artemisinin sensitivity, suggesting that artemisinins interact with the thapsigargin-binding cleft of susceptible SERCAs.
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Acknowledgements
This study was supported by the Wellcome Trust (grant 074395). We thank D. Fidock for invaluable discussions.
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Uhlemann, AC., Cameron, A., Eckstein-Ludwig, U. et al. A single amino acid residue can determine the sensitivity of SERCAs to artemisinins. Nat Struct Mol Biol 12, 628–629 (2005). https://doi.org/10.1038/nsmb947
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DOI: https://doi.org/10.1038/nsmb947
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