ArticleScience advances2025
Human P2X4 receptor gating is modulated by a stable cytoplasmic cap and a unique allosteric pocket.
Article in Science advances, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Long-Chain S-Acylation Is a Key Modulator During the Macrophage Inflammatory Response.Molecular & cellular proteomics : MCP · 2026Article
- Mechanisms of ligand recognition and channel opening for P2X2 receptors in lipid nanodiscs.Science advances · 2026Article
- Positive allosteric modulator activity of ginsenosides is restricted to P2X7 and P2X4 receptors.Purinergic signalling · 2026Article
- Novel P2X4 Receptor Antagonist MRS4719 Improves Ischemia/reperfusion Injury in Mice.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Article
- Methodological guidelines for P2X receptor assays and data interpretation.Cell death & disease · 2026Review
- Cryo-EM structures of human P2X2/3 heteromer channel reveal the structural basis of ligand selectivity.Science advances · 2026Article
- Structure of the human P2X3 receptor reveals the basis for subtype-selective inhibition by sivopixant.PLoS biology · 2026Article
- Mechanisms of ligand recognition and channel opening for P2X2 receptors in lipid nanodiscs.bioRxiv : the preprint server for biology · 2025Article
- Discovery of an allosteric binding site for anthraquinones at the human P2X4 receptor.Nature communications · 2025Article
- Bayesian inference of functional asymmetry in the homotrimeric ligand-gated ion channel P2XCommunications biology · 2025Article
- Subtype-specific structural features of the hearing loss-associated human P2X2 receptor.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
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Abstract
P2X receptors (P2XRs) are adenosine 5'-triphosphate (ATP)-gated ion channels comprising homomeric and heteromeric trimers of seven subtypes (P2X1-P2X7) that confer different rates of desensitization. The helical recoil model of P2XR desensitization proposes stability of the cytoplasmic cap sets the rate of desensitization, but timing of its formation is unclear for slow-desensitizing P2XRs. We report cryo-electron microscopy structures of full-length wild-type human P2X4 receptor in apo closed, antagonist-bound inhibited, and ATP-bound desensitized states. Because the apo closed and antagonist-bound inhibited state structures of this slow-desensitizing P2XR include an intact cytoplasmic cap while the ATP-bound desensitized state structure does not, the cytoplasmic cap is formed before agonist binding. Furthermore, structural and functional data suggest the cytoplasmic cap is stabilized by lipids to modulate desensitization, and P2X4 is modified by glycosylation and palmitoylation. Last, our antagonist-bound inhibited state structure reveals features specific to the allosteric ligand-binding pocket in human receptors that facilitates development of small-molecule modulators.
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