Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor.
Nat Commun
; 12(1): 3763, 2021 06 18.
Article
em En
| MEDLINE
| ID: mdl-34145245
ABSTRACT
The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric Gs. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Peptídeo 1 Semelhante ao Glucagon
/
Receptor do Peptídeo Semelhante ao Glucagon 1
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article