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

Yi-Lynn Liang, Maryam Khoshouei, Mazdak Radjainia, Yan Zhang, Alisa Glukhova, Jeffrey Tarrasch, David Thal, Sebastian G. B. Furness, George Christopoulos, Thomas Coudrat, Rado Danev, Wolfgang Baumeister , Laurence J Miller, Arthur Christopoulos, Brian Kobilka, Denise Wootten, Georgios Skiniotis, Patrick Sexton

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201 Citations (Scopus)

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 Gα s βÎ 3 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 Gα 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 Gβ subunit. This structure provides a new framework for understanding G-protein-coupled receptor function.

Original languageEnglish
Pages (from-to)118-123
Number of pages6
JournalNature
Volume546
Issue number7656
DOIs
Publication statusPublished - 1 Jun 2017

Cite this

Liang, Y-L., Khoshouei, M., Radjainia, M., Zhang, Y., Glukhova, A., Tarrasch, J., ... Sexton, P. (2017). Phase-plate cryo-EM structure of a class B GPCR-G-protein complex. Nature, 546(7656), 118-123. https://doi.org/10.1038/nature22327