Structural characterization of the Plasmodium falciparum lactate transporter PfFNT alone and in complex with antimalarial compound MMV007839 reveals its inhibition mechanism

PLoS Biol. 2021 Sep 9;19(9):e3001386. doi: 10.1371/journal.pbio.3001386. eCollection 2021 Sep.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / chemistry*
  • Antimalarials / pharmacology*
  • Cryoelectron Microscopy
  • Formates
  • Lactic Acid / metabolism
  • Malaria, Falciparum
  • Monocarboxylic Acid Transporters / antagonists & inhibitors*
  • Monocarboxylic Acid Transporters / chemistry
  • Nitrites
  • Plasmodium falciparum / drug effects
  • Protozoan Proteins / antagonists & inhibitors
  • Protozoan Proteins / chemistry
  • Structure-Activity Relationship


  • Antimalarials
  • Formates
  • Monocarboxylic Acid Transporters
  • Nitrites
  • Protozoan Proteins
  • Lactic Acid

Grants and funding

This work was supported by National Key R&D Program of China 2016YFA0502700 from Ministry of Science and Technology of the People’s Republic of China ( to DD and Beijing Nova Program Z201100006820039 from Beijing Municipal Science & Technology Commission ( to CY. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.