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Abstract

Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, such as osteoporosis, diabetes and obesity. Here we report the structure of a full-length class B receptor, the calcitonin receptor, in complex with peptide ligand and heterotrimeric G alpha(s)beta gamma protein determined by Volta phase-plate single-particle cryo-electron microscopy. The peptide agonist engages the receptor by binding to an extended hydrophobic pocket facilitated by the large outward movement of the extracellular ends of transmembrane helices 6 and 7. This conformation is accompanied by a 60 degrees kink in helix 6 and a large outward movement of the intracellular end of this helix, opening the bundle to accommodate interactions with the alpha 5-helix of G alpha(s). Also observed is an extended intracellular helix 8 that contributes to both receptor stability and functional G-protein coupling via an interaction with the G beta subunit. This structure provides a new framework for understanding G-protein-coupled receptor function.