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Nature. 2017 Jun 1;546(7656):118-123. doi: 10.1038/nature22327. Epub 2017 Apr 24.

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

Author information

1
Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052 Victoria, Australia.
2
Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
3
Department of Biochemistry and Molecular Biology, Monash University, Clayton, 3800 Victoria, Australia.
4
Life Sciences Institute and Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109-2216, USA.
5
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, Arizona 85259, USA.
6
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.

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 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.

PMID:
28437792
PMCID:
PMC5832441
DOI:
10.1038/nature22327
[Indexed for MEDLINE]
Free PMC Article

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