7ydq
Structure of PfNT1(Y190A)-GFP in complex with GSK4
Structural highlights
FunctionENT1_PLAF7 Sodium-independent nucleoside and nucleobase transporter with a broad substrate specificity (PubMed:10744765, PubMed:10861212, PubMed:16751273, PubMed:18639591, PubMed:36977719). Plays a key role in the utilization of host purine sources by P.falciparum during intraerythrocytic development enabling parasite growth in the presence of physiological concentrations of adenosine, inosine, guanine, guanosine, xanthine and hypoxanthine (PubMed:16751273, PubMed:18639591). Essential for parasite transition from ring to trophozoite or from trophozoite to schizont stage but not for erythrocyte invasion by merozoites (PubMed:16751273).[1] [2] [3] [4] [5] GFP_AEQVI Energy-transfer acceptor. Its role is to transduce the blue chemiluminescence of the protein aequorin into green fluorescent light by energy transfer. Fluoresces in vivo upon receiving energy from the Ca(2+)-activated photoprotein aequorin. Publication Abstract from PubMedBy 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. 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 Nat Commun. 2023 Mar 28;14(1):1727. doi: 10.1038/s41467-023-37411-1. PMID:36977719[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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