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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Amino Acid Substitution / genetics*
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Animals
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Artemisinins / metabolism*
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Artemisinins / toxicity
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Calcium-Transporting ATPases / antagonists & inhibitors
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Calcium-Transporting ATPases / genetics*
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Calcium-Transporting ATPases / metabolism
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Drug Resistance / physiology*
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Mitochondrial Proton-Translocating ATPases / antagonists & inhibitors
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Mitochondrial Proton-Translocating ATPases / genetics*
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Mitochondrial Proton-Translocating ATPases / metabolism
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Models, Molecular*
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Molecular Sequence Data
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Oocytes
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Plasmodium falciparum / metabolism*
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Plasmodium falciparum / physiology
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Sarcoplasmic Reticulum Calcium-Transporting ATPases
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Sequence Alignment
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Xenopus laevis
Substances
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Artemisinins
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Mitochondrial Proton-Translocating ATPases
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Sarcoplasmic Reticulum Calcium-Transporting ATPases
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Calcium-Transporting ATPases