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 M. Thal, Sebastian G. B. Furness, George Christopoulos, Thomas Coudrat, Radostin Danev, Wolfgang Baumeister, Laurence J. Miller, Arthur Christopoulos, Brian K. Kobilka, Denise Wootten (), Georgios Skiniotis () and Patrick M. Sexton ()
Additional contact information
Yi-Lynn Liang: Monash Institute of Pharmaceutical Sciences, Monash University
Maryam Khoshouei: Max Planck Institute of Biochemistry
Mazdak Radjainia: Monash University
Yan Zhang: University of Michigan Medical School
Alisa Glukhova: Monash Institute of Pharmaceutical Sciences, Monash University
Jeffrey Tarrasch: University of Michigan Medical School
David M. Thal: Monash Institute of Pharmaceutical Sciences, Monash University
Sebastian G. B. Furness: Monash Institute of Pharmaceutical Sciences, Monash University
George Christopoulos: Monash Institute of Pharmaceutical Sciences, Monash University
Thomas Coudrat: Monash Institute of Pharmaceutical Sciences, Monash University
Radostin Danev: Max Planck Institute of Biochemistry
Wolfgang Baumeister: Max Planck Institute of Biochemistry
Laurence J. Miller: Mayo Clinic
Arthur Christopoulos: Monash Institute of Pharmaceutical Sciences, Monash University
Brian K. Kobilka: Stanford University School of Medicine
Denise Wootten: Monash Institute of Pharmaceutical Sciences, Monash University
Georgios Skiniotis: University of Michigan Medical School
Patrick M. Sexton: Monash Institute of Pharmaceutical Sciences, Monash University

Nature, 2017, vol. 546, issue 7656, 118-123

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature22327

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