9e3p

Cryo-EM structure of the human P2X7 receptor in the UB-MBX-46-bound inhibited state

spinqualitylabelsall models 9e3p, resolution 2.53Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9e3p is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.53Å Ligands: A1BD9, GDP, NA, NAG, PLM, Y01, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease P2RX7_HUMAN B-cell chronic lymphocytic leukemia. Function P2RX7_HUMAN ATP-gated nonselective transmembrane cation channel that requires high millimolar concentrations of ATP for activation (PubMed:17483156, PubMed:25281740, PubMed:9038151). Upon ATP binding, it rapidly opens to allow the influx of small cations Na(+) and Ca(2+), and the K(+) efflux (PubMed:17483156, PubMed:20453110, PubMed:28235784, PubMed:39262850). Also has the ability to form a large pore in the cell membrane, allowing the passage of large cationic molecules (PubMed:17483156). In microglia, may mediate NADPH transport across the plasma membrane (PubMed:39142135). 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 (By similarity). Activates death pathways leading to apoptosis and autophagy (PubMed:21821797, PubMed:23303206, PubMed:28326637). Activates death pathways leading to pyroptosis (By similarity).[UniProtKB:Q9Z1M0] Shows ion channel activity but no macropore function. Non-functional channel. Non-functional channel. Publication Abstract from PubMed The 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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