| Structural highlights
9e3m 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 2.48Å |
| Ligands: | , , , , , |
| 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][1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] Shows ion channel activity but no macropore function.[12] Non-functional channel.[13] Non-functional channel.[14]
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[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Riedel T, Schmalzing G, Markwardt F. Influence of extracellular monovalent cations on pore and gating properties of P2X7 receptor-operated single-channel currents. Biophys J. 2007 Aug 1;93(3):846-58. PMID:17483156 doi:10.1529/biophysj.106.103614
- ↑ Adinolfi E, Cirillo M, Woltersdorf R, Falzoni S, Chiozzi P, Pellegatti P, Callegari MG, Sandonà D, Markwardt F, Schmalzing G, Di Virgilio F. Trophic activity of a naturally occurring truncated isoform of the P2X7 receptor. FASEB J. 2010 Sep;24(9):3393-404. PMID:20453110 doi:10.1096/fj.09-153601
- ↑ Gu BJ, Saunders BM, Petrou S, Wiley JS. P2X(7) is a scavenger receptor for apoptotic cells in the absence of its ligand, extracellular ATP. J Immunol. 2011 Sep 1;187(5):2365-75. PMID:21821797 doi:10.4049/jimmunol.1101178
- ↑ Gu BJ, Baird PN, Vessey KA, Skarratt KK, Fletcher EL, Fuller SJ, Richardson AJ, Guymer RH, Wiley JS. A rare functional haplotype of the P2RX4 and P2RX7 genes leads to loss of innate phagocytosis and confers increased risk of age-related macular degeneration. FASEB J. 2013 Apr;27(4):1479-87. PMID:23303206 doi:10.1096/fj.12-215368
- ↑ Robinson LE, Shridar M, Smith P, Murrell-Lagnado RD. Plasma membrane cholesterol as a regulator of human and rodent P2X7 receptor activation and sensitization. J Biol Chem. 2014 Nov 14;289(46):31983-31994. PMID:25281740 doi:10.1074/jbc.M114.574699
- ↑ Karmakar M, Katsnelson MA, Dubyak GR, Pearlman E. Neutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1β secretion in response to ATP. Nat Commun. 2016 Feb 15;7:10555. PMID:26877061 doi:10.1038/ncomms10555
- ↑ Pippel A, Stolz M, Woltersdorf R, Kless A, Schmalzing G, Markwardt F. Localization of the gate and selectivity filter of the full-length P2X7 receptor. Proc Natl Acad Sci U S A. 2017 Mar 14;114(11):E2156-E2165. PMID:28235784 doi:10.1073/pnas.1610414114
- ↑ Sadovnick AD, Gu BJ, Traboulsee AL, Bernales CQ, Encarnacion M, Yee IM, Criscuoli MG, Huang X, Ou A, Milligan CJ, Petrou S, Wiley JS, Vilariño-Güell C. Purinergic receptors P2RX4 and P2RX7 in familial multiple sclerosis. Hum Mutat. 2017 Jun;38(6):736-744. PMID:28326637 doi:10.1002/humu.23218
- ↑ Mou YJ, Li FM, Zhang R, Sheng R, Han R, Zhang ZL, Hu LF, Zhao YZ, Wu JC, Qin ZH. The P2X7 receptor mediates NADPH transport across the plasma membrane. Biochem Biophys Res Commun. 2024 Dec 10;737:150500. PMID:39142135 doi:10.1016/j.bbrc.2024.150500
- ↑ Markwardt F, Schön EC, Raycheva M, Malisetty A, Hawro Yakoob S, Berthold M, Schmalzing G. Two serial filters control P2X7 cation selectivity, Ser342 in the central pore and lateral acidic residues at the cytoplasmic interface. PNAS Nexus. 2024 Aug 23;3(9):pgae349. PMID:39262850 doi:10.1093/pnasnexus/pgae349
- ↑ Rassendren F, Buell GN, Virginio C, Collo G, North RA, Surprenant A. The permeabilizing ATP receptor, P2X7. Cloning and expression of a human cDNA. J Biol Chem. 1997 Feb 28;272(9):5482-6. PMID:9038151 doi:10.1074/jbc.272.9.5482
- ↑ Adinolfi E, Cirillo M, Woltersdorf R, Falzoni S, Chiozzi P, Pellegatti P, Callegari MG, Sandonà D, Markwardt F, Schmalzing G, Di Virgilio F. Trophic activity of a naturally occurring truncated isoform of the P2X7 receptor. FASEB J. 2010 Sep;24(9):3393-404. PMID:20453110 doi:10.1096/fj.09-153601
- ↑ Cheewatrakoolpong B, Gilchrest H, Anthes JC, Greenfeder S. Identification and characterization of splice variants of the human P2X7 ATP channel. Biochem Biophys Res Commun. 2005 Jun 24;332(1):17-27. PMID:15896293 doi:10.1016/j.bbrc.2005.04.087
- ↑ Feng YH, Li X, Wang L, Zhou L, Gorodeski GI. A truncated P2X7 receptor variant (P2X7-j) endogenously expressed in cervical cancer cells antagonizes the full-length P2X7 receptor through hetero-oligomerization. J Biol Chem. 2006 Jun 23;281(25):17228-17237. PMID:16624800 doi:10.1074/jbc.M602999200
- ↑ 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, Müller CE, Kolocouris A, Vázquez S, Mansoor SE. A polycyclic scaffold identified by structure-based drug design effectively inhibits the human P2X7 receptor. Nat Commun. 2025 Sep 15;16(1):8283. PMID:40954149 doi:10.1038/s41467-025-62643-8
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