The class B glucagon-like peptide-1 (GLP-1) G protein-coupled receptor is a major target for the treatment of type 2 diabetes and obesity1. Endogenous and mimetic GLP-1 peptides exhibit biased agonism—a difference in functional selectivity—that may provide improved therapeutic outcomes1. Here we describe the structure of the human GLP-1 receptor in complex with the G protein-biased peptide exendin-P5 and a Gαs heterotrimer, determined at a global resolution of 3.3 Å. At the extracellular surface, the organization of extracellular loop 3 and proximal transmembrane segments differs between our exendin-P5-bound structure and previous GLP-1-bound GLP-1 receptor structure2. At the intracellular face, there was a six-degree difference in the angle of the Gαs–α5 helix engagement between structures, which was propagated across the G protein heterotrimer. In addition, the structures differed in the rate and extent of conformational reorganization of the Gαs protein. Our structure provides insights into the molecular basis of biased agonism.

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The work was supported by the Monash University Ramaciotti Centre for Cryo-Electron Microscopy, the National Health and Medical Research Council of Australia (NHMRC) project grants (1061044, 1065410, 1120919 and 1126857), NHMRC program grant (1055134), Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020347) and Shanghai Science and Technology Development Fund (15DZ2291600). P.M.S., A.C., D.W. and C.K. are NHMRC Principal Research, Senior Principal Research, Career Development and CJ Martin Fellows, respectively. S.L. received the Postgraduate Overseas Study Fellowship from CAS. We thank J. Plitzko, G. Christopoulos, V. Julita, J. Michaelis, X. Zhang, P. Thompson and M. Liu for assay and technical support and B. Kobilka for technical advice and comments on the manuscript.

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Author notes

    • Yi-Lynn Liang
    • , Maryam Khoshouei
    •  & Alisa Glukhova

    These authors contributed equally to this work.


  1. Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Victoria, Australia

    • Yi-Lynn Liang
    • , Alisa Glukhova
    • , Sebastian G. B. Furness
    • , Peishen Zhao
    • , Lachlan Clydesdale
    • , Cassandra Koole
    • , Tin T. Truong
    • , David M. Thal
    • , Mazdak Radjainia
    • , Laurence J. Miller
    • , Arthur Christopoulos
    • , Patrick M. Sexton
    •  & Denise Wootten
  2. Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany

    • Maryam Khoshouei
    • , Radostin Danev
    •  & Wolfgang Baumeister
  3. University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China

    • Saifei Lei
    •  & Ming-Wei Wang
  4. The National Center for Drug Screening and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

    • Saifei Lei
    •  & Ming-Wei Wang
  5. FEI, 5651 GG Eindhoven, The Netherlands

    • Mazdak Radjainia
  6. School of Pharmacy, Fudan University, Shanghai 201203, China

    • Ming-Wei Wang
    •  & Patrick M. Sexton
  7. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, Arizona 85259, USA

    • Laurence J. Miller


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Y.-L.L. established the GLP-1R complex expression and purification strategy, expressed and purified the complex, and performed negative stain EM and data acquisition/analysis; Y.-L.L. and M.R. performed preliminary cryo-EM screening; M.K. performed cryo-sample preparation and phase plate imaging to acquire EM data and performed EM map calculations; A.G. built the model and performed refinement; A.G., C.K. and D.M.T. performed pharmacological assays; L.C., T.T.T. and S.L. performed the mutagenesis studies; S.G.B.F. and P.Z. designed and performed the G protein BRET assays; R.D. and W.B. organized and developed the Volta phase plate cryo-EM data acquisition strategy; Y.-L.L., M.K., A.G., S.G.B.F., P.Z., L.C., C.K., D.M.T., T.T.T., S.L., A.C., P.M.S. and D.W. performed data analysis; S.G.B.F., P.Z., C.K., A.C., L.J.M., M.-W.W. and A.C. assisted with data interpretation and preparation of the manuscript; Y.L.L., M.K., A.G., P.M.S. and D.W. interpreted data and wrote the manuscript; P.M.S. and D.W. supervised the project.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Patrick M. Sexton or Denise Wootten.

Reviewer Information Nature thanks R. Glaeser, F. Marshall and J. Mayer 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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    Life Sciences Reporting Summary

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    Supplementary Table

    This file contains Supplemental Data Table 1. Cryo-EM data collection, refinement and validation statistics.


  1. 1.

    Morph between inactive and active receptor rearrangement of conserved networks upon GLP-1R binding to ExP5.

    Morph between inactive GLP-1R (homology model of the GLP-1R inactive TM generated using the closely related GCGR (4L6R) as a template) and the ExP5 active receptor reveals major rearrangement of the central hydrogen bond network, the hydrophobic network and the two ground state stabilising hydrogen bond networks (summarised in Ext. Data Figure 5) are associated with large scale conformational movements within the TM bundle (particularly TM6) upon receptor activation.

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