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Structure paper

TitleStructural basis of the substrate recognition and inhibition mechanism of Plasmodium falciparum nucleoside transporter PfENT1.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 1727, Year 2023
Publish dateMar 28, 2023
AuthorsChen 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 / Dong Deng /
PubMed AbstractBy lacking de novo purine biosynthesis enzymes, Plasmodium falciparum requires purine nucleoside uptake from host cells. The indispensable nucleoside transporter ENT1 of P. falciparum facilitates ...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.
External linksNat Commun / PubMed:36977719 / PubMed Central
MethodsEM (single particle)
Resolution3.11 - 4.04 Å
Structure data

32618

7wn0

EMDB-32618, PDB-7wn0:
Structure of PfENT1(Y190A) in complex with nanobody 19
Method: EM (single particle) / Resolution: 3.64 Å

32619

7wn1

EMDB-32619, PDB-7wn1:
Structure of PfNT1(Y190A) in complex with nanobody 48 and inosine
Method: EM (single particle) / Resolution: 3.11 Å

33756

7ydq

EMDB-33756, PDB-7ydq:
Structure of PfNT1(Y190A)-GFP in complex with GSK4
Method: EM (single particle) / Resolution: 4.04 Å

Chemicals

ChemComp-NOS:
INOSINE

ChemComp-IRX:
5-methyl-N-[2-(2-oxidanylideneazepan-1-yl)ethyl]-2-phenyl-1,3-oxazole-4-carboxamide

Source
  • plasmodium falciparum (malaria parasite P. falciparum)
  • vicugna pacos (alpaca)
  • plasmodium falciparum 3d7 (eukaryote)
  • aequorea victoria (jellyfish)
KeywordsTRANSPORT PROTEIN / malaria / nucleoside transporter / Equilibrative nucleoside transporter / inosine / MEMBRANE PROTEIN / GSK4

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