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

Research output: Contribution to journalArticleResearchpeer-review

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, Yi-Lynn ; Khoshouei, Maryam ; Radjainia, Mazdak ; Zhang, Yan ; Glukhova, Alisa ; Tarrasch, Jeffrey ; Thal, David ; Furness, Sebastian G. B. ; Christopoulos, George ; Coudrat, Thomas ; Danev, Rado ; Baumeister , Wolfgang ; Miller, Laurence J ; Christopoulos, Arthur ; Kobilka, Brian ; Wootten, Denise ; Skiniotis, Georgios ; Sexton, Patrick. / Phase-plate cryo-EM structure of a class B GPCR-G-protein complex. In: Nature. 2017 ; Vol. 546, No. 7656. pp. 118-123.
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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 Gα s β{\^I} 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.",
author = "Yi-Lynn Liang and Maryam Khoshouei and Mazdak Radjainia and Yan Zhang and Alisa Glukhova and Jeffrey Tarrasch and David Thal and Furness, {Sebastian G. B.} and George Christopoulos and Thomas Coudrat and Rado Danev and Wolfgang Baumeister and Miller, {Laurence J} and Arthur Christopoulos and Brian Kobilka and Denise Wootten and Georgios Skiniotis and Patrick Sexton",
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Liang, Y-L, Khoshouei, M, Radjainia, M, Zhang, Y, Glukhova, A, Tarrasch, J, Thal, D, Furness, SGB, Christopoulos, G, Coudrat, T, Danev, R, Baumeister , W, Miller, LJ, Christopoulos, A, Kobilka, B, Wootten, D, Skiniotis, G & Sexton, P 2017, 'Phase-plate cryo-EM structure of a class B GPCR-G-protein complex' Nature, vol. 546, no. 7656, pp. 118-123. https://doi.org/10.1038/nature22327

Phase-plate cryo-EM structure of a class B GPCR-G-protein complex. / Liang, Yi-Lynn; Khoshouei, Maryam; Radjainia, Mazdak; Zhang, Yan; Glukhova, Alisa; Tarrasch, Jeffrey; Thal, David; Furness, Sebastian G. B.; Christopoulos, George; Coudrat, Thomas; Danev, Rado; Baumeister , Wolfgang; Miller, Laurence J; Christopoulos, Arthur; Kobilka, Brian; Wootten, Denise; Skiniotis, Georgios; Sexton, Patrick.

In: Nature, Vol. 546, No. 7656, 01.06.2017, p. 118-123.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Liang, Yi-Lynn

AU - Khoshouei, Maryam

AU - Radjainia, Mazdak

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AU - Glukhova, Alisa

AU - Tarrasch, Jeffrey

AU - Thal, David

AU - Furness, Sebastian G. B.

AU - Christopoulos, George

AU - Coudrat, Thomas

AU - Danev, Rado

AU - Baumeister , Wolfgang

AU - Miller, Laurence J

AU - Christopoulos, Arthur

AU - Kobilka, Brian

AU - Wootten, Denise

AU - Skiniotis, Georgios

AU - Sexton, Patrick

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AB - 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.

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Liang Y-L, Khoshouei M, Radjainia M, Zhang Y, Glukhova A, Tarrasch J et al. Phase-plate cryo-EM structure of a class B GPCR-G-protein complex. Nature. 2017 Jun 1;546(7656):118-123. https://doi.org/10.1038/nature22327