Article | Published:

Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein

Nature volume 546, pages 248253 (08 June 2017) | Download Citation

Abstract

Glucagon-like peptide 1 (GLP-1) is a hormone with essential roles in regulating insulin secretion, carbohydrate metabolism and appetite. GLP-1 effects are mediated through binding to the GLP-1 receptor (GLP-1R), a class B G-protein-coupled receptor (GPCR) that signals primarily through the stimulatory G protein Gs. Class B GPCRs are important therapeutic targets; however, our understanding of their mechanism of action is limited by the lack of structural information on activated and full-length receptors. Here we report the cryo-electron microscopy structure of the peptide-activated GLP-1R–Gs complex at near atomic resolution. The peptide is clasped between the N-terminal domain and the transmembrane core of the receptor, and further stabilized by extracellular loops. Conformational changes in the transmembrane domain result in a sharp kink in the middle of transmembrane helix 6, which pivots its intracellular half outward to accommodate the α5-helix of the Ras-like domain of Gs. These results provide a structural framework for understanding class B GPCR activation through hormone binding.

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Acknowledgements

We thank M. Su for support with electron microscopy, W. Weis for comments on model refinement, and S. Reedtz-Runge, T. Egebjerg and N. Kulahin for suggesting the rabbit GLP-1R as a candidate for structural studies. This work was supported by NIH grants DK090165 and NS092695 (to G.S.) and R44 DK106942 (to ConfometRx).

Author information

Author notes

    • Georgios Skiniotis

    Present address: Department of Molecular and Cellular Physiology, and Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA.

    • Yan Zhang
    •  & Bingfa Sun

    These authors contributed equally to this work.

Affiliations

  1. Life Sciences Institute and Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA

    • Yan Zhang
    • , Hongli Hu
    • , Qianhui Qu
    • , Jeffrey T. Tarrasch
    •  & Georgios Skiniotis
  2. ConfometRx, 3070 Kenneth St, Santa Clara, California 95054, USA

    • Bingfa Sun
    • , Dan Feng
    • , Matthew Chu
    • , Shane Li
    • , Tong Sun Kobilka
    •  & Brian K. Kobilka
  3. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA

    • Brian K. Kobilka

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Contributions

Y.Z. performed cryo-EM map calculation, model building and refinement; B.S. established GLP-1–GLP-1R–Gs complex formation strategy; B.S., D.F. and M.C. expressed and purified the complex; S.L. prepared Gs protein; H.H., Q.Q., Y.Z. acquired cryo-EM data; J.T.T. assisted in specimen screening by negative-stain EM; Y.Z., B.K.K. and G.S. analysed the data and wrote the manuscript; T.S.K, B.K.K. and G.S. supervised the project.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Brian K. Kobilka or Georgios Skiniotis.

Reviewer Information Nature thanks R. Glaeser, D. Poyner and T. Schwartz for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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https://doi.org/10.1038/nature22394

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