A single amino acid residue can determine the sensitivity of SERCAs to artemisinins

Nat Struct Mol Biol. 2005 Jul;12(7):628-9. doi: 10.1038/nsmb947. Epub 2005 Jun 5.

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

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution / genetics*
  • Animals
  • Artemisinins / metabolism*
  • Artemisinins / toxicity
  • Calcium-Transporting ATPases / antagonists & inhibitors
  • Calcium-Transporting ATPases / genetics*
  • Calcium-Transporting ATPases / metabolism
  • Drug Resistance / physiology*
  • Mitochondrial Proton-Translocating ATPases / antagonists & inhibitors
  • Mitochondrial Proton-Translocating ATPases / genetics*
  • Mitochondrial Proton-Translocating ATPases / metabolism
  • Models, Molecular*
  • Molecular Sequence Data
  • Oocytes
  • Plasmodium falciparum / metabolism*
  • Plasmodium falciparum / physiology
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Sequence Alignment
  • Xenopus laevis

Substances

  • Artemisinins
  • Mitochondrial Proton-Translocating ATPases
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Calcium-Transporting ATPases