Ligand recognition, unconventional activation, and G protein coupling of the prostaglandin E₂ receptor EP2 subtype

Selective modulation of the heterotrimeric G protein α S subunit–coupled prostaglandin E₂ (PGE₂) receptor EP2 subtype is a promising therapeutic strategy for osteoporosis, ocular hypertension, neurodegenerative diseases, and cardiovascular disorders. Here, we report the cryo–electron microscopy structure of the EP2-G_s complex with its endogenous agonist PGE₂ and two synthesized agonists, taprenepag and evatanepag (CP-533536). These structures revealed distinct features of EP2 within the EP receptor family in terms of its unconventional receptor activation and G protein coupling mechanisms, including activation in the absence of a typical W^6.48 “toggle switch” and coupling to G_s via helix 8. Moreover, inspection of the agonist-bound EP2 structures uncovered key motifs governing ligand selectivity. Our study provides important knowledge for agonist recognition and activation mechanisms of EP2 and will facilitate the rational design of drugs targeting the PGE₂ signaling system.