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Author(s): Nathan Robertson [1]; Mathieu Rappas [1]; Andrew S. Dor [1]; Jason Brown [1]; Giovanni Bottegoni [1]; Markus Koglin [1]; Julie Cansfield [1]; Ali Jazayeri [1]; Robert M. Cooke [1]; [...]

Author(s): Ali Jazayeri; Mathieu Rappas; Alastair J. H. Brown; James Kean; James C. Errey; Nathan J. Robertson; Cdric Fiez-Vandal; Stephen P. Andrews; Miles Congreve; Andrea Bortolato; Jonathan S. Mason; Asma [...]

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 -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., Author(s): Ali Jazayeri [1]; Mathieu Rappas [1]; Alastair J. H. Brown [1]; James Kean [1]; James C. Errey [1]; Nathan J. Robertson [1]; Cdric Fiez-Vandal [1]; Stephen P. Andrews [1]; [...]