Cryo-EM structures of human P2X2/3 heteromer channel reveal the structural basis of ligand selectivity.

Authors

Xinyu Cheng, Wei Zhang, Tong Che, Hongmin Guo, Weiwei Nan, Yuting Zhang, Ying Fu, Shuangyan Wan, Jin Zhang

Published in

Science advances. Volume 12. Issue 14. Pages eaea9268. Apr 03, 2026. Epub Apr 03, 2026.

Abstract

P2X3 receptors are key mediators of adenosine 5'-triphosphate (ATP)-evoked cough reflexes and validated drug targets, but first-generation antagonists such as gefapixant are limited by off-target inhibition of P2X2/3 heteromers in taste pathways. Here, we report the first cryo-electron microscopy (cryo-EM) structures of the human P2X2/3 heteromer in multiple ligand-bound states. The structures resolve its debated stoichiometries (1:2 and 2:1), reveal asymmetric pore organization, and identify heteromer-specific rearrangements that modulate ATP binding and gating. Structural and functional analyses show that gefapixant binds a conserved interfacial allosteric pocket, explaining its poor selectivity and taste-related side effects, whereas the next-generation antagonist camlipixant exploits a divergent vestibular site unique to P2X3, conferring >10,000-fold selectivity and improved tolerability. These findings establish a structural framework for P2X2/3 assembly and drug recognition and provide a roadmap for rational design of selective P2X modulators with enhanced safety and efficacy.

PMID:
41931608
Bibliographic data and abstract were imported from PubMed on 04 Apr 2026.

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