Structural insights into the human P2X1 receptor and ligand interactions.

Humans Receptors, Purinergic P2X1 / metabolism Adenosine Triphosphate / metabolism Ligands Cryoelectron Microscopy Purinergic P2X Receptor Antagonists / pharmacology HEK293 Cells Protein Binding Binding Sites Models, Molecular Benzenesulfonates

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
28 Sep 2024
Historique:
received: 08 04 2024
accepted: 20 09 2024
medline: 29 9 2024
pubmed: 29 9 2024
entrez: 28 9 2024
Statut: epublish

Résumé

The P2X1 receptor is a trimeric ligand-gated ion channel that plays an important role in urogenital and immune functions, offering the potential for new drug treatments. However, progress in this area has been hindered by limited structural information and a lack of well-characterised tool compounds. In this study, we employ cryogenic electron microscopy (cryo-EM) to elucidate the structures of the P2X1 receptor in an ATP-bound desensitised state and an NF449-bound closed state. NF449, a potent P2X1 receptor antagonist, engages the receptor distinctively, while ATP, the endogenous ligand, binds in a manner consistent with other P2X receptors. To explore the molecular basis of receptor inhibition, activation, and ligand interactions, key residues involved in ligand and metal ion binding were mutated. Radioligand binding assays with [

Identifiants

DOI: 10.1038/s41467-024-52776-7 PMID: 39341830
pubmed: 39341830
doi: 10.1038/s41467-024-52776-7
pii: 10.1038/s41467-024-52776-7
doi:

Substances chimiques

Receptors, Purinergic P2X1 0
Adenosine Triphosphate 8L70Q75FXE
Ligands 0
Purinergic P2X Receptor Antagonists 0
4,4,',4'',4'''-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis(benzene-1,3-disulfonate) 0
Benzenesulfonates 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

8418

Subventions

Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : 1196951

Informations de copyright

© 2024. The Author(s).

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Auteurs

Felix M Bennetts (FM)

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
Australian Research Council Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.

Hariprasad Venugopal (H)

Ramaciotti Centre for Cryo-Electron Microscopy, Monash University, Clayton, VIC, Australia.
ORCID: 0000-0001-5230-2973

Alisa Glukhova (A)

Australian Research Council Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
Structural Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
ORCID: 0000-0003-4146-965X

Jesse I Mobbs (JI)

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia. jesse.mobbs@monash.edu.
Australian Research Council Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia. jesse.mobbs@monash.edu.
ORCID: 0000-0001-6979-1427

Sabatino Ventura (S)

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia. sab.ventura@monash.edu.
ORCID: 0000-0002-0621-7724

David M Thal (DM)

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia. david.thal@monash.edu.
Australian Research Council Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia. david.thal@monash.edu.
ORCID: 0000-0002-0325-2524

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Structural insights into the human P2X1...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs aux neuromédiateurs › Récepteurs purinergiques › Récepteurs purinergiques P2 › Récepteurs purinergiques P2X › Récepteurs purinergiques P2X1 › Structural insights into the human P2X1...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléotides › Ribonucléotides › Nucléotides adényliques › Adénosine triphosphate › Structural insights into the human P2X1...
questionsmedicales.fr › Actions chimiques et utilisations › Utilisations spécialisées de produits chimiques › Produits chimiques de laboratoire › Ligands › Structural insights into the human P2X1...
questionsmedicales.fr › Techniques d'investigation › Microscopie électronique › Cryomicroscopie électronique › Structural insights into the human P2X1...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Agents neuromédiateurs › Agents purinergiques › Antagonistes purinergiques › Antagonistes des récepteurs purinergiques P2 › Antagonistes des récepteurs purinergiques P2X › Structural insights into the human P2X1...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HEK293 › Structural insights into the human P2X1...
questionsmedicales.fr › Métabolisme › Liaison aux protéines › Structural insights into the human P2X1...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Sites de fixation › Structural insights into the human P2X1...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles moléculaires › Structural insights into the human P2X1...
questionsmedicales.fr › Composés chimiques organiques › Composés du soufre › Acides du soufre › Acides sulfoniques › Acides arènesulfoniques › Arènesulfonates › Benzènesulfonates › Structural insights into the human P2X1...