Mapping a novel positive allosteric modulator binding site in the central vestibule region of human P2X7

Bidula, S, Cromer, B, Walpole, S, Angulo, J and Stokes, L 2019, 'Mapping a novel positive allosteric modulator binding site in the central vestibule region of human P2X7', Scientific Reports, vol. 9, no. 1, pp. 1-11.


Document type: Journal Article
Collection: Journal Articles

Title Mapping a novel positive allosteric modulator binding site in the central vestibule region of human P2X7
Author(s) Bidula, S
Cromer, B
Walpole, S
Angulo, J
Stokes, L
Year 2019
Journal name Scientific Reports
Volume number 9
Issue number 1
Start page 1
End page 11
Total pages 11
Publisher Nature
Abstract P2X7 receptors are important in the regulation of inflammatory responses and immune responses to intracellular pathogens such as Mycobacterium tuberculosis and Toxoplasma gondii. Enhancement of P2X7 receptor responses may be useful in pathogen clearance particularly in individuals with defective microbial killing mechanisms. Ginsenosides from Panax ginseng have been discovered to act as positive allosteric modulators of P2X7. Here we describe a novel modulator binding site identified by computational docking located in the central vestibule of P2X7 involving S60, D318, and L320 in the lower body β-sheets lining the lateral portals. Potentiation of ATP-mediated responses by ginsenosides CK and Rd caused enhanced ionic currents, Ca2+ influx and YOPRO-1 uptake in stably transfected HEK-293 cells (HEK-hP2X7) plus enhanced cell death responses. Potentiation of ATP responses by CK and Rd was markedly reduced by mutations S59A, S60A, D318L and L320A supporting the proposed allosteric modulator binding site. Furthermore, mutation of the conserved residues S60 and D318 led to alterations in P2X7 response and a higher sensitivity to ATP in the absence of modulators suggesting residues in the connecting rods play an important role in regulating P2X7 gating. Identification of this novel binding site location in the central vestibule may also be relevant for structurally similar channels.
Subject Receptors and Membrane Biology
Keyword(s) Ion-Channel
Receptor
Ivermectin
Ginseng
Inflammasome
Pharmacology
Polymorphism
Activation
DOI - identifier 10.1038/s41598-019-39771-5
Copyright notice © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License
ISSN 2045-2322
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