ArticleProceedings of the National Academy of Sciences of the United States of America2011
Agonist trapped in ATP-binding sites of the P2X2 receptor.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 55 citations in OpenAlex.
- SIFa peptidergic neurons orchestrate the internal states and energy balance of male Drosophila melanogaster.PLoS biology · 2025Article
- Subtype-Specific Ligand Binding and Activation Gating in Homomeric and Heteromeric P2X Receptors.Biomolecules · 2024Article
- Unlocking the therapeutic potential of P2X7 receptor: a comprehensive review of its role in neurodegenerative disorders.Frontiers in pharmacology · 2024Review
- P2X2 receptor subunit interfaces are missense variant hotspots, where mutations tend to increase apparent ATP affinity.British journal of pharmacology · 2022Article
- Molecular determinants for agonist recognition and discrimination in P2X2 receptors.The Journal of general physiology · 2019Article
- The ASIC3/P2X3 cognate receptor is a pain-relevant and ligand-gated cationic channel.Nature communications · 2018Article
- P2X receptors.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2016Review
- A Highly Conserved Salt Bridge Stabilizes the Kinked Conformation of β2,3-Sheet Essential for Channel Function of P2X4 Receptors.The Journal of biological chemistry · 2016Article
- Photo-switchable tweezers illuminate pore-opening motions of an ATP-gated P2X ion channel.eLife · 2016Article
- Characterization of ATPase Activity of P2RX2 Cation Channel.Frontiers in physiology · 2016Article
- Insights into the channel gating of P2X receptors from structures, dynamics and small molecules.Acta pharmacologica Sinica · 2016Review
- Key sites for P2X receptor function and multimerization: overview of mutagenesis studies on a structural basis.Current medicinal chemistry · 2015Review
- Conformational flexibility of the agonist binding jaw of the human P2X3 receptor is a prerequisite for channel opening.British journal of pharmacology · 2014Article
- Regulation of ATP-gated P2X channels: from redox signaling to interactions with other proteins.Antioxidants & redox signaling · 2014Review
- Ectodomain movements of an ATP-gated ion channel (P2X2 receptor) probed by disulfide locking.The Journal of biological chemistry · 2014Article
- Structural and molecular modeling features of P2X receptors.International journal of molecular sciences · 2014Review
- Optical control of trimeric P2X receptors and acid-sensing ion channels.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Article
- Inherent dynamics of head domain correlates with ATP-recognition of P2X4 receptors: insights gained from molecular simulations.PloS one · 2014Article
- Exploring the ATP-binding site of P2X receptors.Frontiers in cellular neuroscience · 2013Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
ATP-gated P2X receptors are trimeric ion channels, as recently confirmed by X-ray crystallography. However, the structure was solved without ATP and even though extracellular intersubunit cavities surrounded by conserved amino acid residues previously shown to be important for ATP function were proposed to house ATP, the localization of the ATP sites remains elusive. Here we localize the ATP-binding sites by creating, through a proximity-dependent "tethering" reaction, covalent bonds between a synthesized ATP-derived thiol-reactive P2X2 agonist (NCS-ATP) and single cysteine mutants engineered in the putative binding cavities of the P2X2 receptor. By combining whole-cell and single-channel recordings, we report that NCS-ATP covalently and specifically labels two previously unidentified positions N140 and L186 from two adjacent subunits separated by about 18 Å in a P2X2 closed state homology model, suggesting the existence of at least two binding modes. Tethering reaction at both positions primes subsequent agonist binding, yet with distinct functional consequences. Labeling of one position impedes subsequent ATP function, which results in inefficient gating, whereas tethering of the other position, although failing to produce gating by itself, enhances subsequent ATP function. Our results thus define a large and dynamic intersubunit ATP-binding pocket and suggest that receptors trapped in covalently agonist-bound states differ in their ability to gate the ion channel.
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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.