title: A single amino acid residue can determine the sensitivity of SERCAs to artemisinins.
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.
authors.affiliation: Department of Cellular and Molecular Medicine, Infectious Diseases, St. George's Hospital Medical School, London SW17 0RE, UK.
authors.forename: Anne-Catrin
authors.initials: AC
authors.lastname: Uhlemann
authors.forename: Angus
authors.initials: A
authors.lastname: Cameron
authors.forename: Ursula
authors.initials: U
authors.lastname: Eckstein-Ludwig
authors.forename: Jorge
authors.initials: J
authors.lastname: Fischbarg
authors.forename: Pavel
authors.initials: P
authors.lastname: Iserovich
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Zuniga
authors.forename: Malcolm
authors.initials: M
authors.lastname: East
authors.forename: Anthony
authors.initials: A
authors.lastname: Lee
authors.forename: Leo
authors.initials: L
authors.lastname: Brady
authors.forename: Richard K
authors.initials: RK
authors.lastname: Haynes
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Krishna
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D037621:Artemisinins / Q000378:metabolism* / Q000633:toxicity; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004351:Drug Resistance / Q000502:physiology*; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009865:Oocytes; D010963:Plasmodium falciparum / Q000378:metabolism* / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D016415:Sequence Alignment; D014982:Xenopus laevis
chemical_list: D037621:Artemisinins; D025261:Mitochondrial Proton-Translocating ATPases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases