Nature
Nature
5 years ago

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

Crystal structure of the GLP-1 receptor bound to a peptide agonist
Ali Jazayeri, Andrea Bortolato, Cédric Fiez-Vandal, Robert M. Cooke, Alastair J. H. Brown, Asma H. Baig, Fiona H. Marshall, Stephen P. Andrews, Miles Congreve, Andrew S. Doré, Mathieu Rappas, Nathan J. Robertson, James Kean, Malcolm Weir, Jonathan S. Mason, James C. Errey, Iryna Teobald
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.

Publisher URL: http://dx.doi.org/10.1038/nature22800

DOI: 10.1038/nature22800

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