Structural basis of the substrate recognition and inhibition mechanism of Plasmodium falciparum nucleoside transporter PfENT1

Chen Wang, Leiye Yu, Jiying Zhang, Yanxia Zhou, Bo Sun, Qingjie Xiao, Minhua Zhang, Huayi Liu, Jinhong Li, Jialu Li, Yunzi Luo, Jie Xu, Zhong Lian, Jingwen Lin, Xiang Wang, Peng Zhang, Li Guo (), Ruobing Ren () and Dong Deng ()
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Chen Wang: Sichuan University
Leiye Yu: Fudan University
Jiying Zhang: Sichuan University
Yanxia Zhou: Sichuan University
Bo Sun: Chinese Academy of Sciences
Qingjie Xiao: Chinese Academy of Sciences
Minhua Zhang: Chinese Academy of Sciences
Huayi Liu: Sichuan University
Jinhong Li: Sichuan University
Jialu Li: Sichuan University
Yunzi Luo: Tianjin University
Jie Xu: Sichuan University
Zhong Lian: Sichuan University
Jingwen Lin: Sichuan University
Xiang Wang: Sichuan University
Peng Zhang: Chinese Academy of Sciences
Li Guo: Sichuan University
Ruobing Ren: Fudan University
Dong Deng: Sichuan University

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract By lacking de novo purine biosynthesis enzymes, Plasmodium falciparum requires purine nucleoside uptake from host cells. The indispensable nucleoside transporter ENT1 of P. falciparum facilitates nucleoside uptake in the asexual blood stage. Specific inhibitors of PfENT1 prevent the proliferation of P. falciparum at submicromolar concentrations. However, the substrate recognition and inhibitory mechanism of PfENT1 are still elusive. Here, we report cryo-EM structures of PfENT1 in apo, inosine-bound, and inhibitor-bound states. Together with in vitro binding and uptake assays, we identify that inosine is the primary substrate of PfENT1 and that the inosine-binding site is located in the central cavity of PfENT1. The endofacial inhibitor GSK4 occupies the orthosteric site of PfENT1 and explores the allosteric site to block the conformational change of PfENT1. Furthermore, we propose a general “rocker switch” alternating access cycle for ENT transporters. Understanding the substrate recognition and inhibitory mechanisms of PfENT1 will greatly facilitate future efforts in the rational design of antimalarial drugs.

Date: 2023
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DOI: 10.1038/s41467-023-37411-1

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