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

Nature (2017-06-01)
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
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Collagenase from Clostridium histolyticum, release of physiologically active rat pancreatic islets tested, Type V, ≥1 FALGPA units/mg solid, >125 CDU/mg solid
Sigma-Aldrich
2-Oleoyl-1-palmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt, ≥98.0% (TLC)

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