ArticleNature communications2025
A polycyclic scaffold identified by structure-based drug design effectively inhibits the human P2X7 receptor.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Pockets to products: a data-driven approach for classification of monoterpene synthases.Digital discovery · 2026Article
- Structural and molecular principles of DAMP biology.Nature structural & molecular biology · 2026Review
- Molecular Hybridization of Clinically Relevant P2X7 Antagonists.ChemMedChem · 2026Article
- P2X7 receptor: An emerging therapeutic target in acute myeloid leukemia (Review).International journal of oncology · 2026Review
- Benzamide derivatives as allosteric ligands of the human and rat P2X7 receptor.Purinergic signalling · 2026Article
- Increased P2X7 level does not affect anxiety or stress-coping behavior in male mice.Purinergic signalling · 2026Article
- Effects of New P2X7R Antagonists on Retinal Inflammatory Degenerative Conditions.Inflammation · 2026Article
- Methodological guidelines for P2X receptor assays and data interpretation.Cell death & disease · 2026Review
- A brain-penetrant P2X7R antagonist mitigates Alzheimer's disease pathology.bioRxiv : the preprint server for biology · 2026Article
- Cryo-EM structures of human P2X2/3 heteromer channel reveal the structural basis of ligand selectivity.Science advances · 2026Article
- Structure of the human P2X3 receptor reveals the basis for subtype-selective inhibition by sivopixant.PLoS biology · 2026Article
- P2X7 receptor-dependent microglia-astrocyte coupling in Alzheimer's disease: from eATP sensing to synaptic and proteostatic failure.Frontiers in aging neuroscience · 2026Review
- Genetic Variations in the P2X7 Receptor: Opportunities and Challenges for Drug Development.International journal of molecular sciences · 2025Review
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Authors and funding
16 authors.
Funding
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.
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