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The class A orphanG protein-coupled receptor （GPCR）, GPR3, hasbeen implicated in a variety of conditions, including Alzheimer’sand premature ovarian failure. GPR3 constitutively couples with Gαs,resulting in the production of cAMP in cells. While tool compoundsand several putative endogenous ligands have emerged for the receptor,its endogenous ligand, if it exists, remains a mystery. As novel potentialdrug targets, the structures of orphan GPCRs have been of increasinginterest, revealing distinct modes of activation, including autoactivation,presence of constitutively activating mutations, or via cryptic ligands.Here, we present a cryo-electron microscopy （cryo-EM） structure ofthe orphan GPCR, GPR3 in complex with DNGαs and Gβ1γ2. The structure revealed clear densityfor a lipid-like ligand that bound within an extended hydrophobicgroove, suggesting that the observed “constitutive activity”was likely due to activation via a lipid that may be ubiquitouslypresent. Analysis of conformational variance within the cryo-EM dataset revealed twisting motions of the GPR3 transmembrane helices thatappeared coordinated with changes in the lipid-like density. We proposea mechanism for the binding of a lipid to its putative orthostericbinding pocket linked to the GPR3 dynamics.
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