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Crystal structure of the GLP-1 receptor bound to a peptide agonist

Author

Listed:
  • Ali Jazayeri

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road)

  • Mathieu Rappas

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road)

  • Alastair J. H. Brown

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road)

  • James Kean

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road)

  • James C. Errey

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road)

  • Nathan J. Robertson

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road)

  • Cédric Fiez-Vandal

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road)

  • Stephen P. Andrews

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road)

  • Miles Congreve

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road)

  • Andrea Bortolato

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road)

  • Jonathan S. Mason

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road)

  • Asma H. Baig

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road)

  • Iryna Teobald

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road)

  • Andrew S. Doré

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road)

  • Malcolm Weir

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road)

  • Robert M. Cooke

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road)

  • Fiona H. Marshall

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road)

Abstract

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.

Suggested Citation

  • 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. Mas, 2017. "Crystal structure of the GLP-1 receptor bound to a peptide agonist," Nature, Nature, vol. 546(7657), pages 254-258, June.
    • Handle: RePEc:nat:nature:v:546:y:2017:i:7657:d:10.1038_nature22800
    DOI: 10.1038/nature22800
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    Cited by:

    1. Shane C. Wright & Aikaterini Motso & Stefania Koutsilieri & Christian M. Beusch & Pierre Sabatier & Alessandro Berghella & Élodie Blondel-Tepaz & Kimberley Mangenot & Ioannis Pittarokoilis & Despoina-, 2023. "GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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