Use of photoaffinity labeling to understand the molecular basis of ligand binding to the secretin receptor

The secretin receptor was the first member of the Class B family of G protein-coupled receptors that was identified in 1991, 89 years after secretin action was first recognized. That report resulted in the introduction of the term hormone and in the birth of the field of endocrinology. The secretin receptor has become prototypic of this receptor family, binding a moderately long linear peptide with a diffuse pharmacophoric domain. Here, we provide a detailed account of the contributions of photoaffinity labeling to establish the molecular basis of natural ligand binding to this receptor, as well as to provide insights into possible mechanisms for receptor activation and initiation of signaling. Each of the themes discussed are also relevant to other members of this physiologically and pharmacologically important receptor family.