Phase-plate cryo-EM structure of a class B GPCR–G-protein complex

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 Gαsβγ 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° kink in helix 6 and a large outward movement of the intracellular end of this helix, opening the bundle to accommodate interactions with the α5-helix of Gαs. Also observed is an extended intracellular helix 8 that contributes to both receptor stability and functional G-protein coupling via an interaction with the Gβ subunit. This structure provides a new framework for understanding G-protein-coupled receptor function. Volta phase-plate cryo-electron microscopy reveals the structure of the full-length calcitonin receptor in complex with its peptide ligand and Gαsβγ. The use of cryo-electron microscopy (cryo-EM) in structural biology has exploded in recent years as it provides structural information at near atomic resolution without the need for crystallization. However, cryo-EM has typically been limited to proteins larger than 200 kDa because of issues with low contrast. Patrick Sexton and colleagues report the structure of the full-length calcitonin receptor in complex with its peptide ligand and Gαsβγ protein by Volta phase-plate single-particle cryo-EM. This is the first G-protein-coupled receptor (GPCR) structure to be solved at high resolution by cryo-EM, the first full-length class B GPCR reported and only the second in complex with the full heterotrimeric G protein. The structure shows the GPCR in the active state and reveals key information about the conformational changes associated with peptide agonist binding and G-protein coupling in class B receptors.