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 language | English |
|---|---|
| Pages (from-to) | 118-123 |
| Number of pages | 6 |
| Journal | Nature |
| Volume | 546 |
| Issue number | 7656 |
| DOIs | |
| Publication status | Published - 1 Jun 2017 |
Cite this
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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 journal › Article › Research › peer-review
TY - JOUR
T1 - Phase-plate cryo-EM structure of a class B GPCR-G-protein complex
AU - Liang, Yi-Lynn
AU - Khoshouei, Maryam
AU - Radjainia, Mazdak
AU - Zhang, Yan
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
PY - 2017/6/1
Y1 - 2017/6/1
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85019746188&partnerID=8YFLogxK
U2 - 10.1038/nature22327
DO - 10.1038/nature22327
M3 - Article
VL - 546
SP - 118
EP - 123
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7656
ER -