7wn0

Structure of PfENT1(Y190A) in complex with nanobody 19

spinqualitylabelsall models 7wn0, resolution 3.64Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7wn0 is a 2 chain structure with sequence from Plasmodium falciparum and Vicugna pacos. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.64Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ENT1_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). Publication Abstract from PubMed 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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