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Structural characterization of the Plasmodium falciparum lactate transporter PfFNT alone and in complex with antimalarial compound MMV007839 reveals its inhibition mechanism.
PLOS Biology ( IF 9.8 ) Pub Date : 2021-09-09 , DOI: 10.1371/journal.pbio.3001386
Xi Peng 1 , Nan Wang 2 , Angqi Zhu 2 , Hanwen Xu 2 , Jialu Li 1 , Yanxia Zhou 1 , Chen Wang 1 , Qingjie Xiao 1 , Li Guo 1 , Fei Liu 1, 3 , Zhi-Jun Jia 1, 3 , Huaichuan Duan 4 , Jianping Hu 4 , Weidan Yuan 1, 5 , Jia Geng 1, 5 , Chuangye Yan 2 , Xin Jiang 6 , Dong Deng 1
Affiliation  

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.

中文翻译:

恶性疟原虫乳酸转运蛋白 PfFNT 单独和与抗疟化合物 MMV007839 复合的结构表征揭示了其抑制机制。

在 2019 年全球 2.29 亿疟疾病例中,恶性疟原虫是最致命的疟疾病原体,占一半以上。 一线抗药性疟原虫菌株的出现和传播在抗击疟疾的斗争中具有挑战性,并提出了对新型冠状病毒的迫切需求抗疟药。恶性疟原虫甲酸-亚硝酸盐转运蛋白 (PfFNT) 是一种潜在的药物靶点,因为它在红细胞内阶段的乳酸流出中起管家作用。针对 PfFNT,MMV007839 被鉴定为一种先导化合物,可在亚微摩尔浓度下杀死寄生虫。在这里,我们展示了 PfFNT 的 2 种低温电子显微镜 (cryo-EM) 结构,一种具有 apo 形式的蛋白质,另一种与 MMV007839 复合,分辨率均为 2.3 Å。得益于高分辨率的结构,
更新日期:2021-09-09
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