7wn0

From Proteopedia
Jump to navigation Jump to search

Structure of PfENT1(Y190A) in complex with nanobody 19Structure of PfENT1(Y190A) in complex with nanobody 19

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).[1] [2] [3] [4] [5]

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[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Carter NS, Ben Mamoun C, Liu W, Silva EO, Landfear SM, Goldberg DE, Ullman B. Isolation and functional characterization of the PfNT1 nucleoside transporter gene from Plasmodium falciparum. J Biol Chem. 2000 Apr 7;275(14):10683-91. PMID:10744765 doi:10.1074/jbc.275.14.10683
  2. ↑ Parker MD, Hyde RJ, Yao SY, McRobert L, Cass CE, Young JD, McConkey GA, Baldwin SA. Identification of a nucleoside/nucleobase transporter from Plasmodium falciparum, a novel target for anti-malarial chemotherapy. Biochem J. 2000 Jul 1;349(Pt 1):67-75. PMID:10861212 doi:10.1042/0264-6021:3490067
  3. ↑ El Bissati K, Zufferey R, Witola WH, Carter NS, Ullman B, Ben Mamoun C. The plasma membrane permease PfNT1 is essential for purine salvage in the human malaria parasite Plasmodium falciparum. Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9286-91. PMID:16751273 doi:10.1073/pnas.0602590103
  4. ↑ El Bissati K, Downie MJ, Kim SK, Horowitz M, Carter N, Ullman B, Ben Mamoun C. Genetic evidence for the essential role of PfNT1 in the transport and utilization of xanthine, guanine, guanosine and adenine by Plasmodium falciparum. Mol Biochem Parasitol. 2008 Oct;161(2):130-9. PMID:18639591 doi:10.1016/j.molbiopara.2008.06.012
  5. ↑ 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. Structural basis of the substrate recognition and inhibition mechanism of Plasmodium falciparum nucleoside transporter PfENT1. Nat Commun. 2023 Mar 28;14(1):1727. PMID:36977719 doi:10.1038/s41467-023-37411-1
  6. ↑ 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. Structural basis of the substrate recognition and inhibition mechanism of Plasmodium falciparum nucleoside transporter PfENT1. Nat Commun. 2023 Mar 28;14(1):1727. PMID:36977719 doi:10.1038/s41467-023-37411-1

7wn0, resolution 3.64Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=7wn0&oldid=4234173"