A single amino acid residue can determine the sensitivity of SERCAs to artemisinins.
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.
Uhlemann
Anne-Catrin
AC
Department of Cellular and Molecular Medicine, Infectious Diseases, St. George's Hospital Medical School, London SW17 0RE, UK.
Cameron
Angus
A
Eckstein-Ludwig
Ursula
U
Fischbarg
Jorge
J
Iserovich
Pavel
P
Zuniga
Felipe A
FA
East
Malcolm
M
Lee
Anthony
A
Brady
Leo
L
Haynes
Richard K
RK
Krishna
Sanjeev
S
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
D037621:Artemisinins; D025261:Mitochondrial Proton-Translocating ATPases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases