biostudies-literatureUnknown14(1)Wu CProstaglandin F_2α (PGF_2α), an endogenous arachidonic acid metabolite, regulates diverse physiological functions in many tissues and cell types through binding and activation of a G-protein-coupled receptor (GPCR), the PGF_2α receptor (FP), which also is the primary therapeutic target for glaucoma and several other diseases. Here, we report cryo-electron microscopy (cryo-EM) structures of the human FP bound to endogenous ligand PGF_2α and anti-glaucoma drugs LTPA and TFPA at global resolutions of 2.67 Å, 2.78 Å, and 3.14 Å. These structures reveal distinct features of FP within the lipid receptor family in terms of ligand binding selectivity, its receptor activation, and G protein coupling mechanisms, including activation in the absence of canonicalNature communications2668https://www.ebi.ac.uk/biostudies/studies/S-EPMC10169810biostudies-literatureLigand-induced activation and G protein coupling of prostaglandin F_2α receptor.PMC10169810Duan JJiang YFan WLi CLi DWu CYou CChen HHe QEric Xu HXu YfalseLigand-induced activation and G protein coupling of prostaglandin F_2α receptor.Prostaglandin F_2α (PGF_2α), an endogenous arachidonic acid metabolite, regulates diverse physiological functions in many tissues and cell types through binding and activation of a G-protein-coupled receptor (GPCR), the PGF_2α receptor (FP), which also is the primary therapeutic target for glaucoma and several other diseases. Here, we report cryo-electron microscopy (cryo-EM) structures of the human FP bound to endogenous ligand PGF_2α and anti-glaucoma drugs LTPA and TFPA at global resolutions of 2.67 Å, 2.78 Å, and 3.14 Å. These structures reveal distinct features of FP within the lipid receptor family in terms of ligand binding selectivity, its receptor activation, and G protein coupling mechanisms, including activation in the absence of canonical2023-01-01T00:00:00Z2023 May2026-05-28T08:23:28.437Z2025-04-05T21:07:59.589ZS-EPMC101698103716089110.1038/s41467-023-38411-x