Modelling G protein-biased agonism using GLP-1 receptor C-terminal mutations.

ABSTRACT:

Background and aim

The glucagon-like peptide-1 receptor (GLP-1R) is a major therapeutic target for type 2 diabetes and obesity. Agonists showing bias in favour of G protein signalling over β-arrestin recruitment and GLP-1R internalisation, e.g. tirzepatide and orforglipron, have favourable clinical efficacy profiles. However, understanding of the effects of biased agonism has been hampered by differences in ligand properties such as affinity, efficacy, stability and pharmacokinetics. Here we used GLP-1R C-tail mutations that inhibit phosphorylation to mimic G protein-biased GLP-1R agonism without the need for ligand modifications.

Methods

Serine doublet phosphorylation sites in the human and mouse GLP-1R C-tails were mutated to alanine. Wild-type and mutant GLP-1Rs were exam

SUBMITTER: Tran HD 

PROVIDER: S-EPMC12925471 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature