Structural insights into probe-dependent positive allosterism of the GLP-1 receptor.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
23
12
2019
accepted:
09
06
2020
pubmed:
22
7
2020
medline:
15
12
2020
entrez:
22
7
2020
Statut:
ppublish
Résumé
Drugs that promote the association of protein complexes are an emerging therapeutic strategy. We report discovery of a G protein-coupled receptor (GPCR) ligand that stabilizes an active state conformation by cooperatively binding both the receptor and orthosteric ligand, thereby acting as a 'molecular glue'. LSN3160440 is a positive allosteric modulator of the GLP-1R optimized to increase the affinity and efficacy of GLP-1(9-36), a proteolytic product of GLP-1(7-36). The compound enhances insulin secretion in a glucose-, ligand- and GLP-1R-dependent manner. Cryo-electron microscopy determined the structure of the GLP-1R bound to LSN3160440 in complex with GLP-1 and heterotrimeric G
Identifiants
pubmed: 32690941
doi: 10.1038/s41589-020-0589-7
pii: 10.1038/s41589-020-0589-7
doi:
Substances chimiques
Glucagon-Like Peptide-1 Receptor
0
glucagon-like peptide-1 (9-36)-amide
0
Glucagon-Like Peptide 1
89750-14-1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1105-1110Références
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