pH-dependence of the Plasmodium falciparum chloroquine resistance transporter is linked to the transport cycle.
Nat Commun
; 14(1): 4234, 2023 07 15.
Article
en En
| MEDLINE
| ID: mdl-37454114
ABSTRACT
The chloroquine resistance transporter, PfCRT, of the human malaria parasite Plasmodium falciparum is sensitive to acidic pH. Consequently, PfCRT operates at 60% of its maximal drug transport activity at the pH of 5.2 of the digestive vacuole, a proteolytic organelle from which PfCRT expels drugs interfering with heme detoxification. Here we show by alanine-scanning mutagenesis that E207 is critical for pH sensing. The E207A mutation abrogates pH-sensitivity, while preserving drug substrate specificity. Substituting E207 with Asp or His, but not other amino acids, restores pH-sensitivity. Molecular dynamics simulations and kinetics analyses suggest an allosteric binding model in which PfCRT can accept both protons and chloroquine in a partial noncompetitive manner, with increased proton concentrations decreasing drug transport. Further simulations reveal that E207 relocates from a peripheral to an engaged location during the transport cycle, forming a salt bridge with residue K80. We propose that the ionized carboxyl group of E207 acts as a hydrogen acceptor, facilitating transport cycle progression, with pH sensing as a by-product.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Malaria Falciparum
/
Antimaláricos
Límite:
Humans
Idioma:
En
Año:
2023
Tipo del documento:
Article