Structural insight into the self-activation and G-protein coupling of P2Y2 receptor

• DOI: 10.1038/s41421-025-00797-x
• Publication Date: 2025-05-13T08:07:10Z
• Authors: Baoliang Lan; Shuhao Zhang; Kai Chen; Shengjie Dai; Jiaqi Fei; Kaixuan Gao; Xiaoou Sun; Bin Lin; Xiangyu Liu
• Keywords: Structural Biology

Abstract Purinergic P2Y2 receptor (P2Y2R) represents a typically extracellular ATP and UTP sensor for mediating purinergic signaling. Despite its importance as pharmacological target, the molecular mechanisms underlying ligand recognition G-protein coupling have remained elusive due to lack of structural information. In this study, we determined cryo-electron microscopy (cryo-EM) structures apo P2Y2R in complex with G q , ATP-bound or o UTP-bound P2Y4R . These reveal similarities distinctions within P2Y family. Furthermore, comprehensive analysis reveals that exhibits promiscuity both proteins. Combining dynamics simulations signaling assays, elucidate by which differentiates pathway-specific through distinct components on intracellular side. Strikingly, identify helix-like segment N-terminus occupies orthosteric ligand-binding pocket P2Y2R, accounting self-activation. Taken together, these findings provide framework understanding activation mechanism encompassing recognition, coupling, novel N-terminus-mediated self-activation mechanism.