The structure of secretin family GPCR peptide ligands: implications for receptor pharmacology and drug development

The secretin family G protein-coupled receptors, characterized by a large N-terminal extracellular domain and seven transmembrane helices, are drug targets in many diseases, including migraine, cardiovascular disease, diabetes, osteoporosis and inflammatory disorders. Their activating ligands are peptides with an average length of 30 amino acids. In this article we review the available structural data for these peptides and how this explains their activity. We emphasize how this information may be used to accelerate the development of new drugs against these receptors.

► We examine structures of secretin family G protein-coupled receptor peptide ligands. ► We examine the importance of structural elements on receptor activation. ► We pinpoint a structural element important for development of new therapeutics. ► We propose a pathway for development of new therapeutics.