Cryo-EM structures of the human P2X1 receptor reveal subtype-specific architecture and antagonism by supramolecular ligand-binding.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
01 Oct 2024
01 Oct 2024
Historique:
received:
03
06
2024
accepted:
16
09
2024
medline:
2
10
2024
pubmed:
2
10
2024
entrez:
1
10
2024
Statut:
epublish
Résumé
P2X receptors are a family of seven trimeric non-selective cation channels that are activated by extracellular ATP to play roles in the cardiovascular, neuronal, and immune systems. Although it is known that the P2X1 receptor subtype has increased sensitivity to ATP and fast desensitization kinetics, an underlying molecular explanation for these subtype-selective features is lacking. Here we report high-resolution cryo-EM structures of the human P2X1 receptor in the apo closed, ATP-bound desensitized, and the high-affinity antagonist NF449-bound inhibited states. The apo closed and ATP-bound desensitized state structures of human P2X1 define subtype-specific properties such as distinct pore architecture and ATP-interacting residues. The NF449-bound inhibited state structure of human P2X1 reveals that NF449 has a unique dual-ligand supramolecular binding mode at the interface of neighboring protomers, inhibiting channel activation by overlapping with the canonical P2X receptor ATP-binding site. Altogether, these data define the molecular pharmacology of the human P2X1 receptor laying the foundation for structure-based drug design.
Identifiants
pubmed: 39353889
doi: 10.1038/s41467-024-52636-4
pii: 10.1038/s41467-024-52636-4
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
8490Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
ID : DP2GM149551
Organisme : U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
ID : R00HL138129
Organisme : American Heart Association (American Heart Association, Inc.)
ID : 24PRE1195450
Informations de copyright
© 2024. The Author(s).
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