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Structural insights into the human P2X1 receptor and ligand interactions
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Abstract
Abstract The P2X1 receptor is a trimeric ligand-gated ion channel that plays a pivotal role in urogenital and immune functions. Consequently, it offers numerous potential indications for novel drug treatments. Unfortunately, the progress of drug discovery targeting the P2X1 receptor has been impeded by the absence of structural information. To gain deeper insights into the binding site of the P2X1 receptor, we employed cryogenic electron microscopy (cryo-EM) to elucidate the structures of the P2X1 receptor in both an ATP-bound desensitised state and an NF449-bound closed state. NF449 is a potent P2X1 receptor antagonist and engages with the receptor in a distinctive manner. To gain insights into the molecular machinery governing receptor inhibition and activation and better understand P2X1 receptor ligand subtype selectivity, critical P2X1 receptor residues involved in ligand binding were mutated. Radioligand binding assays with [ 3 H]-α,β-methylene ATP and intracellular calcium influx were employed to assess the effect of these mutations on ligand binding and receptor activation, thereby validating key ligand-receptor interactions. This research expands our understanding of the P2X1 receptor structure at a molecular level and opens new avenues for in silico drug design targeting the P2X1 receptor.
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Metadata
- Authors
- Bennetts, F. M., Venugopal, H., Glukhova, A., Mobbs, J. I., Ventura, S., & Thal, D. M.
- Affiliations
- Australian Research Council (AU)
- Monash University (AU)
- Corresponding author
- Mobbs, Jesse I.
- Ventura, Sabatino
- Thal, David M.
- ORCID
- Venue
- Nature Communications
- Published
- 2024-09-28
- Volume
- 15
- Issue
- 1
- Pages
- 8418-8418
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC11439047
- OpenAlex
- W4402940303
- Cited by
- 14
- References
- 1
- Citations by year
- 2026: 10 · 2025: 3 · 2024: 1
- FWCI
- 3.97
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Department of Health | National Health and Medical Research Council (1196951)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- P2X1 receptor, ligand-gated ion channels, ATP binding, NF449, receptor antagonists, closed state, ligand-receptor interactions, metal ion binding, site-directed mutagenesis, radioligand binding, calcium influx, therapeutic target, receptor structure
- MeSH terms
- Adenosine Triphosphate, Benzenesulfonates, Binding Sites, Humans, Ligands, Models, Molecular, Protein Binding, Cryoelectron Microscopy, HEK293 Cells, Receptors, Purinergic P2X1, Purinergic P2X Receptor Antagonists
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