ArticleProceedings of the National Academy of Sciences of the United States of America2018
Druggable negative allosteric site of P2X3 receptors.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 115 citations in OpenAlex.
- Safety, Pharmacodynamics, and Pharmacokinetics of P2X3 Receptor Antagonist Eliapixant (BAY 1817080) in Healthy Subjects: Double-Blind Randomized Study.Clinical pharmacokinetics · 2022Trial
- Targeting frizzled receptors (FZDs) for anti-tumor therapy: From orthosteric to allosteric inhibition.Acta pharmaceutica Sinica. B · 2026Review
- Positive allosteric modulator activity of ginsenosides is restricted to P2X7 and P2X4 receptors.Purinergic signalling · 2026Article
- 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
- Vitamin B6 (Pyridoxal 5' Phosphate) antagonises carotid body P2X3 receptors in hypertension.Cardiovascular research · 2026Article
- Generalised Hodgkin-Huxley model captures human P2X and AMPA receptor currents.The Journal of physiology · 2026Article
- 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
- Understanding interspecies drug response variations between human and rodent P2X7 receptors.Nature communications · 2025Article
- Mechanism of capsaicin entry into buried vanilloid sites in TRPV1.Nature chemical biology · 2025Article
- A Chemically Induced CRISPR/dCas13Journal of medicinal chemistry · 2025Article
- Structural basis of the multiple ligand binding mechanisms of the P2X1 receptor.Acta pharmacologica Sinica · 2025Article
- Identification of New Human P2X7 Antagonists Using Ligand- and Structure-Based Virtual Screening.Journal of chemical information and modeling · 2025Article
- Mycobacterial Phenolic Glycolipid Triggers ATP-Mediated Neuronal P2X3 Signaling and Cough.bioRxiv : the preprint server for biology · 2025Article
- Comprehensive insights into potential roles of purinergic P2 receptors on diseases: Signaling pathways involved and potential therapeutics.Journal of advanced research · 2025Review
- Human P2X4 receptor gating is modulated by a stable cytoplasmic cap and a unique allosteric pocket.Science advances · 2025Article
- Mechanistic insights into the selective targeting of P2X3 receptor by camlipixant antagonist.The Journal of biological chemistry · 2025Article
- A shared mechanism for TNP-ATP recognition by members of the P2X receptor family.Computational and structural biotechnology journal · 2024Article
- Ionotropic purinergic receptor 7 (P2X7) channel structure and pharmacology provides insight regarding non-nucleotide agonism.Channels (Austin, Tex.) · 2024Review
Corrections and comments
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Authors and funding
14 authors at 7 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Allosteric modulation provides exciting opportunities for drug discovery of enzymes, ion channels, and G protein-coupled receptors. As cation channels gated by extracellular ATP, P2X receptors have attracted wide attention as new drug targets. Although small molecules targeting P2X receptors have entered into clinical trials for rheumatoid arthritis, cough, and pain, negative allosteric modulation of these receptors remains largely unexplored. Here, combining X-ray crystallography, computational modeling, and functional studies of channel mutants, we identified a negative allosteric site on P2X3 receptors, fostered by the left flipper (LF), lower body (LB), and dorsal fin (DF) domains. Using two structurally analogous subtype-specific allosteric inhibitors of P2X3, AF-353 and AF-219, the latter being a drug candidate under phase II clinical trials for refractory chronic cough and idiopathic pulmonary fibrosis, we defined the molecular interactions between the drugs and receptors and the mechanism by which allosteric changes in the LF, DF, and LB domains modulate ATP activation of P2X3. Our detailed characterization of this druggable allosteric site should inspire new strategies to develop P2X3-specific allosteric modulators for clinical use.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.