PLoS Biology (Sep 2021)

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

  • Xi Peng,
  • Nan Wang,
  • Angqi Zhu,
  • Hanwen Xu,
  • Jialu Li,
  • Yanxia Zhou,
  • Chen Wang,
  • Qingjie Xiao,
  • Li Guo,
  • Fei Liu,
  • Zhi-Jun Jia,
  • Huaichuan Duan,
  • Jianping Hu,
  • Weidan Yuan,
  • Jia Geng,
  • Chuangye Yan,
  • Xin Jiang,
  • Dong Deng

DOI
https://doi.org/10.1371/journal.pbio.3001386
Journal volume & issue
Vol. 19, no. 9
p. e3001386

Abstract

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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.