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G-protein-coupled receptors (GPCRs) are transmembrane proteins that transduce extracellular stimuli into intracellular events. While central to physiology and drug discovery, approximately 100 GPCRs remain orphan, limiting insights into their biology. We establish a generalizable photo-cross-linking-assisted GPCR deorphanization platform that leverages site-specifically incorporated photo-cross-linkers for interface-selective ligand capture from native biological samples. We systematically demonstrate the sensitivity, specificity and broad applicability of our system using multiple GPCR–ligand pairs and further deorphanize GPR50 with the neuropeptide Little-LEN (L-LEN) as its endogenous ligand. L-LEN selectively binds GPR50 and modulates cellular activities through downstream Gαi signaling in tissue. In behaving mice, L-LEN functionally coordinates with GPR50 to regulate energy expenditure and thermogenesis, mechanistically through brain–adipose cross-talk, whereas their deficiency increased the likelihood of torpor following challenges. In summary, we develop an efficient platform for GPCR deorphanization from native samples, and the deorphanization of GPR50 provides insights into its function and drug discovery. In an effort to deorphanize G-protein-coupled receptors, a photo-cross-linking platform was established to capture ligands from complex samples. Little-LEN was identified as a ligand for GPR50, which coordinately regulates body metabolism.
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