Endogenous lipid activated G protein-coupled receptors: Emerging structural features from crystallography and molecular dynamics simulations

► We compare two Class A GPCR structures, the S1-P1R and rhodopsin, both known to bind lipid-derived endogenous ligands. ► We find that EC loop and N-termini packing of both receptors isolate the ligand binding pocket from the extracellular milieu. ► We find that identified lipid portals in both receptors allow ligand entry between TM helices from the lipid bilayer. ► We compare these results with the Cannabinoid CB1 and CB2 receptors which also bind lipid-derived endogenous ligands. ► We conclude that ligand entry via a lipid bilayer portal may be a signature feature of endogenous lipid Class A GPCRs.