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Adv."],"published-print":{"date-parts":[[2026,4,3]]},"abstract":"<jats:p>P2X3 receptors are key mediators of adenosine 5\u2032-triphosphate (ATP)\u2013evoked 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\u2013electron 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 &gt;10,000-fold selectivity and improved tolerability. 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