Cryo-EM structures of human P2X2/3 heteromer channel reveal the structural basis of ligand selectivity - PubMed
19 hours ago
- #Ligand selectivity
- #Cryo-EM structures
- #P2X2/3 heteromer
- First cryo-EM structures of human P2X2/3 heteromer in multiple ligand-bound states reveal its stoichiometries (1:2 and 2:1) and asymmetric pore organization.
- The study identifies heteromer-specific structural changes affecting ATP binding and gating, providing a structural basis for understanding ligand selectivity.
- Gefapixant binds a conserved interfacial allosteric pocket, leading to poor selectivity and taste-related side effects due to off-target inhibition of P2X2/3.
- Camlipixant targets a divergent vestibular site unique to P2X3, offering over 10,000-fold selectivity and improved tolerability compared to first-generation antagonists.
- These findings establish a structural framework for P2X2/3 assembly and drug recognition, aiding rational design of selective P2X modulators for enhanced safety and efficacy.