• A Corrigendum to this article was published on 12 July 2017


Glucagon-like peptide 1 (GLP-1) regulates glucose homeostasis through the control of insulin release from the pancreas. GLP-1 peptide agonists are efficacious drugs for the treatment of diabetes. To gain insight into the molecular mechanism of action of GLP-1 peptides, here we report the crystal structure of the full-length GLP-1 receptor bound to a truncated peptide agonist. The peptide agonist retains an α-helical conformation as it sits deep within the receptor-binding pocket. The arrangement of the transmembrane helices reveals hallmarks of an active conformation similar to that observed in class A receptors. Guided by this structural information, we design peptide agonists with potent in vivo activity in a mouse model of diabetes.

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We thank various colleagues past and present who have helped with the project. In particular we would like to acknowledge the contribution of K. Hollenstein, M. Koglin and C. Larner. We thank G. Brown for his help with coordinating peptide synthesis and radio-labelling and C. Scully for his assistance with the GRID analysis. We are grateful to R. Owen, J. Waterman and D. Axford at I24, Diamond Light Source, Oxford, UK for technical support.

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Author notes

    • Ali Jazayeri
    • , Mathieu Rappas
    •  & Alastair J. H. Brown

    These authors contributed equally to this work.


  1. Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, UK

    • Ali Jazayeri
    • , Mathieu Rappas
    • , Alastair J. H. Brown
    • , James Kean
    • , James C. Errey
    • , Nathan J. Robertson
    • , Cédric Fiez-Vandal
    • , Stephen P. Andrews
    • , Miles Congreve
    • , Andrea Bortolato
    • , Jonathan S. Mason
    • , Asma H. Baig
    • , Iryna Teobald
    • , Andrew S. Doré
    • , Malcolm Weir
    • , Robert M. Cooke
    •  & Fiona H. Marshall


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J.K., N.J.R. and A.J. carried out the conformational thermostabilization of constructs and determined the stability of the StaR in a panel of reagents/additives. A.H.B. and I.T. carried out the in vitro pharmacology. A.J.H.B. managed the in vivo studies. M.C. and S.P.A. designed the novel peptides, aided by A.B. and J.S.M. who designed the homology models and carried out in silico analyses of peptide binding. M.R. and J.C.E. designed the crystallization construct, and with C.F.V. performed and optimized protein expression and purification. M.R. and C.F.V. performed and optimized protein crystallization. M.R. and A.S.D. harvested crystals, collected and processed X-ray diffraction data, and solved and refined the structure. Project management was carried out by A.J., R.M.C., F.H.M. and M.W. The manuscript was prepared by M.R., A.J., A.S.D., A.J.H.B., M.C., R.M.C. and F.H.M. All authors contributed to the final editing and approval of the manuscript.

Competing interests

All authors are employees of Heptares Therapeutics Ltd and are shareholders in Sosei Group Corporation.

Corresponding author

Correspondence to Fiona H. Marshall.

Reviewer Information Nature thanks T. Schwartz, C. Siebold and the other anonymous reviewer(s) 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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