5NX2

Crystal structure of thermostabilised full-length GLP-1R in complex with a truncated peptide agonist at 3.7 A resolution

Summary for 5NX2

• Entry DOI: 10.2210/pdb5nx2/pdb
• Descriptor: Glucagon-like peptide 1 receptor, truncated peptide agonist, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: 7tm, gpcr, signalling protein, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 52088.24

Authors

Rappas, M.,Jazayeri, A.,Brown, A.J.H.,Kean, J.,Errey, J.C.,Robertson, N.,Fiez-Vandal, C.,Andrews, S.P.,Congreve, M.,Bortolato, A.,Mason, J.S.,Baig, A.H.,Teobald, I.,Dore, A.S.,Weir, M.,Cooke, R.M.,Marshall, F.H. (deposition date: 2017-05-09, release date: 2017-06-14, Last modification date: 2024-01-17)

Primary citation

Jazayeri, A.,Rappas, M.,Brown, A.J.H.,Kean, J.,Errey, J.C.,Robertson, N.J.,Fiez-Vandal, C.,Andrews, S.P.,Congreve, M.,Bortolato, A.,Mason, J.S.,Baig, A.H.,Teobald, I.,Dore, A.S.,Weir, M.,Cooke, R.M.,Marshall, F.H.
Crystal structure of the GLP-1 receptor bound to a peptide agonist.
Nature, 546:254-258, 2017

PubMed 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.

PubMed: 28562585
DOI: 10.1038/nature22800

Experimental method

X-RAY DIFFRACTION (3.7 Å)