Coin, I. et al. Cell 155, 1258–1269 (2013).

G protein–coupled receptors (GPCRs) are involved in major cellular functions, but these seven-transmembrane-helix proteins are notoriously difficult to study. An important question is how class B GPCRs such as corticotropin releasing factor receptor type 1 (CRF1R) interact with their peptide ligands. Coin et al. used genetically encodable cross-linking amino acids to study how CRF1R binds its ligand on the membrane of a live cell. They introduced the photo-cross-linking amino acid Azi into CRF1R, allowing them to map the ligand-binding site on the receptor. They also determined the position of the ligand in the binding pocket by incorporating the chemical cross-linking amino acid Ffact into CRF1R; Ffact reacts specifically with a cysteine residue in the ligand. The resulting spatial restraints allowed them to build a model for peptide ligand binding to CRF1R.