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

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 no...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: 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
Formato: article
Lenguaje:EN
Publicado: Public Library of Science (PLoS) 2021
Materias:
Acceso en línea:https://doaj.org/article/9f4f058d8df14e138116686afae63c4d
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
Descripción
Sumario: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.