Abstract
Plasmodium falciparum, the deadliest causal agent of malaria, caused more than half of the 229 million malaria cases worldwide in 2019. The emergence and spreading of frontline drug-resistant Plasmodium strains are challenging to overcome in the battle against malaria and raise urgent demands for novel antimalarial agents. The P. falciparum formate–nitrite transporter (PfFNT) is a potential drug target due to its housekeeping role in lactate efflux during the intraerythrocytic stage. Targeting PfFNT, MMV007839 was identified as a lead compound that kills parasites at submicromolar concentrations. Here, we present 2 cryogenic-electron microscopy (cryo-EM) structures of PfFNT, one with the protein in its apo form and one with it in complex with MMV007839, both at 2.3 Å resolution. Benefiting from the high-resolution structures, our study provides the molecular basis for both the lactate transport of PfFNT and the inhibition mechanism of MMV007839, which facilitates further antimalarial drug design.
Highlights
Malaria remains a worldwide life-threatening disease, leading to an estimated 229 million infections and 409,000 deaths worldwide in 2019 [1]
250 mM sodium lactate was incubated with P. falciparum formate–nitrite transporter (PfFNT) before grid preparation, no extra density for lactate was found, which might be attributed to the low affinity between lactate and PfFNT
The P. falciparum lactate transporter PfFNT is an essential component of the glucose–lactate transport cycle for intraerythrocytic Plasmodium parasites
Summary
Malaria remains a worldwide life-threatening disease, leading to an estimated 229 million infections and 409,000 deaths worldwide in 2019 [1]. Plasmodium falciparum, one of the 5 agents of human malaria, is responsible for more than half of the total infections globally and most the deaths in WHO African region, representing the deadliest form of Plasmodium.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have