EMD-32619

Single-particle
3.11 Å
EMD-32619 Deposition: 17/01/2022
Map released: 01/02/2023
Last modified: 16/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-32619

Structure of PfNT1(Y190A) in complex with nanobody 48 and inosine

EMD-32619

Single-particle
3.11 Å
EMD-32619 Deposition: 17/01/2022
Map released: 01/02/2023
Last modified: 16/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Plasmodium falciparum, Vicugna pacos
Sample: Structure of PfNT1(Y190A) in complex with nanobody 48 and inosine
Fitted models: 7wn1 (Avg. Q-score: 0.545)

Deposition Authors: Wang C, Deng D
Structural basis of the substrate recognition and inhibition mechanism of Plasmodium falciparum nucleoside transporter PfENT1.
Wang C, Yu L, Zhang J, Zhou Y, Sun B , Xiao Q, Zhang M, Liu H , Li J, Li J, Luo Y , Xu J, Lian Z , Lin J , Wang X, Zhang P, Guo L, Ren R , Deng D
(2023) Nat Commun , 14 , 1727 - 1727
PUBMED: 36977719
DOI: doi:10.1038/s41467-023-37411-1
ISSN: 2041-1723
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.