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, Patrick M. Sexton

Research output: Contribution to journalArticle

210 Scopus citations

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 (US)
Pages (from-to)118-123
Number of pages6
JournalNature
Volume546
Issue number7656
DOIs
StatePublished - Jun 1 2017

    Fingerprint

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Liang, Y. L., Khoshouei, M., Radjainia, M., Zhang, Y., Glukhova, A., Tarrasch, J., Thal, D. M., Furness, S. G. B., Christopoulos, G., Coudrat, T., Danev, R., Baumeister, W., Miller, L. J., Christopoulos, A., Kobilka, B. K., Wootten, D., Skiniotis, G., & Sexton, P. M. (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