7ydq

From Proteopedia

(Difference between revisions)

Current revision

Structure of PfNT1(Y190A)-GFP in complex with GSK4

Structural highlights

7ydq is a 1 chain structure with sequence from Aequorea victoria and Plasmodium falciparum 3D7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 4.04Å
Ligands:
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] 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 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

↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7ydq"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 7ydq is ON HOLD
+==Structure of PfNT1(Y190A)-GFP in complex with GSK4==
+<StructureSection load='7ydq' size='340' side='right'caption='[[7ydq]], [[Resolution|resolution]] 4.04&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[7ydq]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Aequorea_victoria Aequorea victoria] and [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7YDQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7YDQ FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 4.04&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IRX:5-methyl-N-[2-(2-oxidanylideneazepan-1-yl)ethyl]-2-phenyl-1,3-oxazole-4-carboxamide'>IRX</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7ydq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ydq OCA], [https://pdbe.org/7ydq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ydq RCSB], [https://www.ebi.ac.uk/pdbsum/7ydq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ydq ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/ENT1_PLAF7 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).<ref>PMID:10744765</ref> <ref>PMID:10861212</ref> <ref>PMID:16751273</ref> <ref>PMID:18639591</ref> <ref>PMID:36977719</ref> [https://www.uniprot.org/uniprot/GFP_AEQVI 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.
+<div style="background-color:#fffaf0;">
+== 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.
-Authors:
+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<ref>PMID:36977719</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 7ydq" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Aequorea victoria]]
+[[Category: Large Structures]]
+[[Category: Plasmodium falciparum 3D7]]
+[[Category: Deng D]]
+[[Category: Li JL]]
+[[Category: Ren RB]]
+[[Category: Wang C]]
+[[Category: Yu LY]]

7ydq

From Proteopedia

Current revision

Structure of PfNT1(Y190A)-GFP in complex with GSK4

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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