Freezing with Light: Photo-Cross-Linking-Assisted Platform Enables GPCR Deorphanization

Despite their success as drug targets, nearly one hundred G protein-coupled receptors (GPCRs) remain orphan without identified endogenous ligands. Defining these ligand-receptor pairs constitute a fundamental prerequisite for understanding receptor biology and rational drug discovery. However, deorphanization remains inherently challenging due to the transient and interface-specific ligand-GPCR interactions, especially for endogenous ones that are embedded within chemically complex environments. This In Focus article highlights a modularly designed platform that integrates site-specific photo-cross-linking reaction with proteomics to enable ligand-GPCR pairing directly in native biological contexts. Using this strategy, neuropeptide L-LEN was identified as the endogenous ligand for GPR50, forming a regulatory axis that controls energy expenditure and thermogenesis through brain-peripheral interactions.