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...

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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:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/9f4f058d8df14e138116686afae63c4d
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spelling	oai:doaj.org-article:9f4f058d8df14e138116686afae63c4d2021-12-02T19:54:36ZStructural characterization of the Plasmodium falciparum lactate transporter PfFNT alone and in complex with antimalarial compound MMV007839 reveals its inhibition mechanism.1544-91731545-788510.1371/journal.pbio.3001386https://doaj.org/article/9f4f058d8df14e138116686afae63c4d2021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.pbio.3001386https://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Plasmodium 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.Xi PengNan WangAngqi ZhuHanwen XuJialu LiYanxia ZhouChen WangQingjie XiaoLi GuoFei LiuZhi-Jun JiaHuaichuan DuanJianping HuWeidan YuanJia GengChuangye YanXin JiangDong DengPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 19, Iss 9, p e3001386 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 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 Structural characterization of the Plasmodium falciparum lactate transporter PfFNT alone and in complex with antimalarial compound MMV007839 reveals its inhibition mechanism.
description	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.
format	article
author	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
author_facet	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
author_sort	Xi Peng
title	Structural characterization of the Plasmodium falciparum lactate transporter PfFNT alone and in complex with antimalarial compound MMV007839 reveals its inhibition mechanism.
title_short	Structural characterization of the Plasmodium falciparum lactate transporter PfFNT alone and in complex with antimalarial compound MMV007839 reveals its inhibition mechanism.
title_full	Structural characterization of the Plasmodium falciparum lactate transporter PfFNT alone and in complex with antimalarial compound MMV007839 reveals its inhibition mechanism.
title_fullStr	Structural characterization of the Plasmodium falciparum lactate transporter PfFNT alone and in complex with antimalarial compound MMV007839 reveals its inhibition mechanism.
title_full_unstemmed	Structural characterization of the Plasmodium falciparum lactate transporter PfFNT alone and in complex with antimalarial compound MMV007839 reveals its inhibition mechanism.
title_sort	structural characterization of the plasmodium falciparum lactate transporter pffnt alone and in complex with antimalarial compound mmv007839 reveals its inhibition mechanism.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/9f4f058d8df14e138116686afae63c4d
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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.

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