9c2c | pdb_00009c2c
Cryo-EM structure of the human P2X1 receptor in the NF449-bound inhibited state
Structural highlights
FunctionP2RX1_HUMAN ATP-gated nonselective transmembrane cation channel permeable to potassium, sodium and with relatively high calcium permeability (PubMed:10440098, PubMed:15056721, PubMed:20699225, PubMed:8834001, PubMed:8961184). Furthermore, CTP functions as a weak affinity agonist for P2RX1 (PubMed:14699168). Plays a role a role in urogenital, immune and cardiovascular function (By similarity). Specifically, plays an important role in neurogenic contraction of smooth muscle of the vas deferens, and therefore is essential for normal male reproductive function (By similarity). In addition, contributes to smooth muscle contractions of the urinary bladder (By similarity). On platelets, contributes to platelet activation and aggregation and thereby, also to thrombosis (By similarity). On neutrophils, it is involved in chemotaxis and in mitigating the activation of circulating cells (PubMed:19635923).[UniProtKB:P51576][1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedP2X 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. Cryo-EM structures of the human P2X1 receptor reveal subtype-specific architecture and antagonism by supramolecular ligand-binding.,Oken AC, Lisi NE, Ditter IA, Shi H, Nechiporuk NA, Mansoor SE Nat Commun. 2024 Oct 1;15(1):8490. doi: 10.1038/s41467-024-52636-4. PMID:39353889[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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