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

Nature volume 546, pages 248–253 (2017)Cite this article

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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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Figure 1: Cryo-EM structure of the human GLP-1–rabbit GLP-1R–Gs complex.
Figure 2: The orthosteric peptide-binding pocket of GLP-1R.
Figure 3: Comparison of active-state GLP-1R with inactive GCGR.
Figure 4: GLP-1R interactions with Gs.
Figure 5: Comparison between activated class A and B receptor conformations.
Figure 6: Polar network rearrangements upon GLP-1R activation.

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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

  1. Georgios Skiniotis

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

  2. Yan Zhang and Bingfa Sun: These authors contributed equally to this work.

Authors and Affiliations

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

    Yan Zhang, Hongli Hu, Qianhui Qu, Jeffrey T. Tarrasch & Georgios Skiniotis

  2. ConfometRx, 3070 Kenneth St, Santa Clara, 95054, California, 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, 94305, California, 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.

Corresponding authors

Correspondence to Brian K. Kobilka or Georgios Skiniotis.

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

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Extended data figures and tables

Extended Data Figure 1 Purification of the hGLP-1–rGLP-1R–Gs complex.

Size-exclusion chromatography profile and corresponding SDS–PAGE gel of the purified hGLP-1–rGLP-1R–Gs complex (‘h’ indicates human and ‘r’ indicates rabbit homologue).

Extended Data Figure 2 Cryo-EM micrograph and 2D class averages of the hGLP-1–rGLP-1R–Gs complex.

a, Cryo-EM micrograph of the activated GLP-1R–Gs complex. Examples of particle projections are circled. Scale bar, 30 nm. b, Representative reference-free two-dimensional averages show distinct secondary structure features for G protein and GLP-1R embedded in MNG detergent micelle. The diameter of the circular windows is 17 nm.

Extended Data Figure 3 Single-particle cryo-EM analysis of the hGLP-1–rGLP-1R–Gs complex.

Flow chart of cryo-EM data processing of the hGLP-1–rGLP-1R–Gs complex, including particle projection selection, classification and 3D density map reconstruction, related to Fig. 1. Details are provided in the Methods section.

Extended Data Figure 4 Resolution of cryo-EM map and validation of the hGLP-1–rGLP-1R–Gs structure.

a, Resolution estimation of the EM map. Gold standard Fourier shell correlation (FSC) curves, showing the overall nominal resolution at 4.1 Å (blue) and 3.9 Å (red) on the stable region including hGLP-1, transmembrane domain and the α5-helix the Gαs Ras-like domain. b, FSC curves of the final refined model versus the final cryo-EM map (full dataset, black), of the outcome of model refinement with a half map versus the same map (red), and of the outcome of model refinement with a half map versus the other half map (green). c, Final three-dimensional density map coloured according to local resolution.

Extended Data Figure 5 A near-atomic resolution model of the hGLP-1–rGLP-1R–Gs complex.

EM density map and model are shown for all seven transmembrane α-helices and helix 8 of rGLP-1R, hGLP-1 peptide and the α5-helix of the Gαs Ras-like domain. Bulky resides are indicated for each segment. The C-terminal half of TM6 exhibits relatively poor density, reflecting its intrinsic flexibility.

Extended Data Figure 6 Features of cryo-EM map before density subtraction.

a, GLP-1R–Gs complex structure docked into cryo-EM density map before micelle density subtraction. Arrows indicate the density corresponding to the linker between the NTD and transmembrane bundle, and Gβγ lipid moiety inserting into the detergent micelle. b, Close-up view in this map shows density connecting helix 8 and Gβ at the position of R419 of helix 8 and G310–H311 of Gβ. Model is coloured as in Fig. 1c.

Extended Data Figure 7 Conformation of ECL2 in class B GPCRs.

a, Close-up view of R299 of ECL2 modelled into the density map at low threshold shows that the Arg side chain reaches into the GLP-1 binding pocket in close proximity to H7 and T11 of the peptide. b, Top-down view of structural overlay of the active GLP-1R transmembrane domain and the inactive CRF1R transmembrane domain (PDB code: 4K5Y) indicates the conformational similarity of ECL2 in the two structures. Detailed views of boxed regions show that W297 and R299 in the active GLP-1R structure adopt similar orientations compared to the equivalent residues in CRF1R. The model of the GLP-1R complex is coloured as in Fig. 1c. CRF1R is coloured purple.

Extended Data Figure 8 Structures of class B GPCR ligands bound to NTDs.

a, Close-up view of structural superposition of the cryo-EM structure of GLP-1–GLP-1R onto crystal structures of N-terminal domain of GLP-1R in complex with peptide exendin-4 (blue; a peptide approved for clinical use) and GLP-1 (purple), respectively. The model of hGLP-1–rGLP-1R–Gs is coloured as in Fig. 1. b, Structural superposition of the cryo-EM structure of GLP-1R NTD bound to GLP-1 to crystal structures of GIPR NTD bound to GIP (blue) and PTH1R NTD bound to PTH (cyan). a, b, Residues S14, S17, S18, F28 and W31 of GLP-1 and equivalent residues in the other peptides are shown in ball and stick (right panel only), highlighting that the corresponding side chains adopt a similar conformation in all available structures. c, Structure-based alignment of selected class B GPCR peptide ligand sequences.

Extended Data Figure 9 Potential NTD–transmembrane bundle interaction, orthosteric agonist binding pocket in GLP-1R and β2AR.

a, Close-up view of the model docked into cryo-EM density map (grey) on the region of NTD–transmembrane bundle interation at low threshold shows the potential hydrogen bond between Q213 of ECL1 and R40 of the NTD α1-helix. b, Overlay of GPCR transmembrane bundles in the activated GLP-1R complex and T4L-β2AR–Gs–Nb35 complex shown in light green and grey, respectively. Cut-through view showing that the GLP-1 peptide N-terminal H7 (orange ball and stick) reaches the same level as the orthosteric agonist BI-167107 (yellow).

Extended Data Figure 10 Comparison of G protein trimer structures from activated GLP-1R–Gs–Nb35 complex and T4L-β2AR–Gs–Nb35 complex with alignment on Gαs Ras-like domain alone, related to Fig. 5.

a, Views of superposition of G protein trimer structures from the activated GLP-1R–Gs structure (Gαs Ras-like domain in gold, Gβ in light blue, Gγ in dark blue) and T4L-β2AR–Gs structure (all coloured in grey). b–d, Schematic representation (b) of recognition between the C terminus of α5-helix (H387–L394) and active receptors of β2AR (c) and GLP-1R (d). The sequence of the C terminus of α5-helix (H387–L394) is shown in the middle in gold. Residues involved in the interaction with α5-helix (H387–L394) in the receptor of β2AR (green box) and GLP-1R (purple box) are shown above and below the schematic, respectively. Hydrophobic interactions are shown in blue and polar interactions in red. Ballesteros–Weinstein numbering in superscript is shown.

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Zhang, Y., Sun, B., Feng, D. et al. Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature 546, 248–253 (2017). https://doi.org/10.1038/nature22394

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