9E3P

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

This is a non-PDB format compatible entry.

Summary for 9E3P

• Entry DOI: 10.2210/pdb9e3p/pdb
• EMDB information: 47493
• Descriptor: P2X purinoceptor 7, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, (1s,3R,4R,6r,8S,9S)-N'-(2-chlorophenyl)-3,4,8,9-tetramethyltetracyclo[4.4.0.0~3,9~.0~4,8~]decane-1-carbohydrazide, ... (10 entities in total)
• Functional Keywords: membrane protein, ion channel, ligand-gated ion channel, p2x receptor, p2xr, allosteric antagonist, agonist
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 221016.14

Authors

Oken, A.C.,Turcu, A.L.,Vazquez, S.,Mansoor, S.E. (deposition date: 2024-10-23, release date: 2025-09-24)

Primary citation

Oken, A.C.,Turcu, A.L.,Tzortzini, E.,Georgiou, K.,Nagel, J.,Westermann, F.G.,Barniol-Xicota, M.,Seidler, J.,Kim, G.R.,Lee, S.D.,Nicke, A.,Kim, Y.C.,Muller, C.E.,Kolocouris, A.,Vazquez, S.,Mansoor, S.E.
A polycyclic scaffold identified by structure-based drug design effectively inhibits the human P2X7 receptor.
Nat Commun, 16:8283-8283, 2025

PubMed Abstract: 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.

PubMed: 40954149
DOI: 10.1038/s41467-025-62643-8

Experimental method

ELECTRON MICROSCOPY (2.53 Å)