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 raising new challenges in the battle against malaria and present an urgent need 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. MMV007839, which targets PfFNT, was identified as a lead compound that kills parasites at sub-micromolar concentrations. Here, Peng et al. present two cryogenic-electron microscopy structures of PfFNT; one with the protein in its unoccupied form and one in complex with MMV007839, both at 2.3 Å resolution. Benefiting from these high-resolution structures, this study provides the molecular basis for both the lactate transport of PfFNT and for the inhibition mechanism of MMV007839, potentially informing further antimalarial drug design. The image shows the overall structure of pentameric PfFNT, from within the plane of the membrane (top left, bottom right) and perpendicular to it (top right, bottom left). The pink circle and ellipse in the latter view indicate the central tunnel of the pentamer and substrate translocation path in one protomer, respectively.

Image Credit: Peng et al.