Comparative genomics, bioinformatics, and biochemical assays enable the pairing of endogenous peptides with orphan GPCRs.

Although there is increasing evidence of the clinical importance of GPCRs that bind to peptide hormones and neuropeptides, there remain more than 100 GPCRs for which the endogenous ligands are unknown. These are referred to as orphan GPCRs (oGPCRs). Foster et al. combined comparative genomics, bioinformatic analysis, and functional assays to pair 17 endogenous peptide ligands with five oGPCRs, as well as identify additional peptides for nine GPCRs that had previously characterized ligands. The authors used comparative genomics to identify peptide precursors and peptides, showing that almost all precursors contained an N-terminal signal peptide, which is required for secretion. Investigation of the characteristic features of class A GPCRs showed distinct structural differences between those that bind to peptide ligands and those that bind to nonpeptide ligands. The authors then mined the entire human proteome to identify peptides with characteristics that made them plausible GPCR ligands. They made a library of synthetic peptide ligands and generated cell lines expressing different oGPCRs that were predicted to be potentially activated by peptides. Last, the authors performed pharmacological and biochemical assays to assess receptor internalization, -arrestin recruitment, and select second messenger generation to identify peptide-receptor pairs that resulted in signaling responses. A number of these peptides and GPCRs have previously been implicated in disorders of the reproductive and nervous systems, among other diseases. Thus, this combinatorial approach has deorphanized five GPCRs, expanded the known peptide-receptor network, and facilitated the future investigation of the roles that these peptides and GPCRs play in physiology and disease.

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Taking care of the orphans - Science