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 M.
AU - Furness, Sebastian G.B.
AU - Christopoulos, George
AU - Coudrat, Thomas
AU - Danev, Radostin
AU - Baumeister, Wolfgang
AU - Miller, Laurence J.
AU - Christopoulos, Arthur
AU - Kobilka, Brian K.
AU - Wootten, Denise
AU - Skiniotis, Georgios
AU - Sexton, Patrick M.
N1 - Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
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.
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U2 - 10.1038/nature22327
DO - 10.1038/nature22327
M3 - Article
C2 - 28437792
AN - SCOPUS:85019746188
SN - 0028-0836
VL - 546
SP - 118
EP - 123
JO - Nature
JF - Nature
IS - 7656
ER -