BPS2026 – Structural insights into the gating of human P2X2 receptor channels

Extracellular ATP activates P2X receptor channels (P2XRs) that are widely expressed in the nervous and immune systems. Structures of P2XRs in detergents reveal an unprecedented mechanism of channel opening that severs subunit interfaces within the transmembrane (TM) region. The mechanisms of agonist recognition and regulation of channel opening also remain enigmatic. Here, we report the high-resolution structures of the human P2X2R (hP2X2R) in lipid nanodiscs in closed, open, desensitized, and intermediate states, revealing that membrane lipids maintain subunit interfaces during channel opening. The ATP binding pocket contains unique features that underlie the requirement for ATP 4- . Finally, we identified a critical regulatory nexus in the extracellular domain (ECD) that couples ATP binding to channel opening. Taken together, these findings establish key principles of gating in P2XRs in a membrane-like environment, providing a framework for future mechanistic studies and therapeutic development.