G protein-coupled receptors (GPCRs) constitute the largest family of cell-surface receptors and are involved in nearly all aspects of biology, yet over 100 human GPCRs have not been definitively paired with endogenous ligands. These ‘orphan receptors’ represent a treasure-trove of unexplored biology and have strong potential to influence human physiology and disease processes.
As part of a large international collaboration, we sought to identify new peptide ligands from the human proteome that activate orphan GPCRs. Capitalising on the wealth of comparative genomics data and leveraging bioinformatic data on human GPCRs, we identified common features of peptide GPCRs and applied statistical and machine learning analyses to identify putative peptide ligands. We then used a multifaceted experimental approach to capture peptide-mediated orphan receptor signalling responses. After extensive validation, we discovered and characterised novel pairings of 17 peptides with five different orphan GPCRs, and identified potential new ligands for nine additional peptide GPCRs. We envisage that these findings will lay the platform for future studies on these peptides and receptors to fully illuminate their roles in human physiology and disease.
