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Activation of the GLP-1 receptor by a non-peptidic agonist.
- Source :
-
Nature [Nature] 2020 Jan; Vol. 577 (7790), pp. 432-436. Date of Electronic Publication: 2020 Jan 08. - Publication Year :
- 2020
-
Abstract
- Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, including diabetes and obesity <superscript>1</superscript> . Structures of active receptors reveal peptide agonists engage deep within the receptor core, leading to an outward movement of extracellular loop 3 and the tops of transmembrane helices 6 and 7, an inward movement of transmembrane helix 1, reorganization of extracellular loop 2 and outward movement of the intracellular side of transmembrane helix 6, resulting in G-protein interaction and activation <superscript>2-6</superscript> . Here we solved the structure of a non-peptide agonist, TT-OAD2, bound to the glucagon-like peptide-1 (GLP-1) receptor. Our structure identified an unpredicted non-peptide agonist-binding pocket in which reorganization of extracellular loop 3 and transmembrane helices 6 and 7 manifests independently of direct ligand interaction within the deep transmembrane domain pocket. TT-OAD2 exhibits biased agonism, and kinetics of G-protein activation and signalling that are distinct from peptide agonists. Within the structure, TT-OAD2 protrudes beyond the receptor core to interact with the lipid or detergent, providing an explanation for the distinct activation kinetics that may contribute to the clinical efficacy of this compound series. This work alters our understanding of the events that drive the activation of class B receptors.
- Subjects :
- Animals
CHO Cells
Cricetinae
Cricetulus
Glucagon-Like Peptide-1 Receptor chemistry
Glucagon-Like Peptide-1 Receptor metabolism
Humans
Isoquinolines chemistry
Kinetics
Models, Molecular
Phenylalanine chemistry
Phenylalanine pharmacology
Protein Structure, Quaternary
Protein Structure, Tertiary
Pyridines chemistry
Structural Homology, Protein
Glucagon-Like Peptide-1 Receptor agonists
Isoquinolines pharmacology
Phenylalanine analogs & derivatives
Pyridines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 577
- Issue :
- 7790
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 31915381
- Full Text :
- https://doi.org/10.1038/s41586-019-1902-z