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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antimalarials / chemistry*
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Antimalarials / pharmacology*
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Cryoelectron Microscopy
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Formates
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Lactic Acid / metabolism
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Malaria, Falciparum
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Monocarboxylic Acid Transporters / antagonists & inhibitors*
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Monocarboxylic Acid Transporters / chemistry
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Nitrites
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Plasmodium falciparum / drug effects
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Protozoan Proteins / antagonists & inhibitors
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Protozoan Proteins / chemistry
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Structure-Activity Relationship
Substances
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Antimalarials
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Formates
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Monocarboxylic Acid Transporters
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Nitrites
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Protozoan Proteins
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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 (
https://service.most.gov.cn) to DD and Beijing Nova Program Z201100006820039 from Beijing Municipal Science & Technology Commission (
https://mis.kw.beijing.gov.cn/out/typt/staticHTML/homePage.html) to CY. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.