9e3q
From Proteopedia
Cryo-EM structure of the mouse P2X7 receptor in the apo closed state
Structural highlights
FunctionP2RX7_MOUSE ATP-gated nonselective transmembrane cation channel. Requires high millimolar-range concentrations of ATP to become activated (PubMed:9849870). ATP binding trigers the rapid opening of the channel and allows Na(+) and Ca(2+) influx and K(+) efflux (By similarity). Has also the ability to form a large pore in the cell membrane, allowing the passage of large cationic molecules (PubMed:25281740). In microglia, may mediate NADPH transport across the plasma membrane (By similarity). In immune cells, P2RX7 acts as a molecular sensor in pathological inflammatory states by detecting and responding to high local concentrations of extracellar ATP. In microglial cells, P2RX7 activation leads to the release of pro-inflammatory cytokines, such as IL-1beta and IL-18, through the activation of the NLRP3 inflammasome and caspase-1 (PubMed:26877061). Cooperates with KCNK6 to activate NLRP3 inflammasome (PubMed:29958799). Activates death pathways leading to apoptosis and autophagy (By similarity). Activates death pathways leading to pyroptosis (PubMed:26572062).[UniProtKB:Q99572][1] [2] [3] [4] [5] Publication Abstract from PubMedThe P2X7 receptor is an ATP-gated ion channel that activates inflammatory pathways involved in diseases such as cancer, atherosclerosis, and neurodegeneration. However, despite the potential benefits of blocking overactive signaling, no P2X7 receptor antagonists have been approved for clinical use. Understanding species-specific pharmacological effects of existing antagonists has been challenging, in part due to the dearth of molecular information on receptor orthologs. Here, to identify distinct molecular features in the human receptor, we determine high-resolution cryo-EM structures of the full-length wild-type human P2X7 receptor in apo closed and ATP-bound open state conformations and draw comparisons with structures of other orthologs. We also report a cryo-EM structure of the human receptor in complex with an adamantane-based inhibitor, which we leverage, in conjunction with functional data and molecular dynamics simulations, to design a potent and selective antagonist with a unique polycyclic scaffold. Functional and structural analysis reveal how this optimized ligand, termed UB-MBX-46, interacts with the classical allosteric pocket of the human P2X7 receptor with subnanomolar potency and high selectivity, revealing its significant therapeutic potential. A polycyclic scaffold identified by structure-based drug design effectively inhibits the human P2X7 receptor.,Oken AC, Turcu AL, Tzortzini E, Georgiou K, Nagel J, Westermann FG, Barniol-Xicota M, Seidler J, Kim GR, Lee SD, Nicke A, Kim YC, Muller CE, Kolocouris A, Vazquez S, Mansoor SE Nat Commun. 2025 Sep 15;16(1):8283. doi: 10.1038/s41467-025-62643-8. PMID:40954149[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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