Structural insights into GLP-1R signaling mechanisms
Glucagon-like peptide-1 receptor (GLP1R) plays a pivotal role in regulating insulin secretion, glucose homeostasis, and satiety, underpinning the outstanding clinical performance and remarkable success of GLP-1R agonists in treating metabolic disorders.
Recent cryo-electron microscopy and crystallographic studies, supported by functional analyses, revealed the intricate signal transduction mechanisms of GLP1R and delineated distinct recognition patterns for both peptidic and small molecule agonists.
The extracellular domain is critical for GLP-1R activation, serving as a key interface for peptides, small molecules, and allosteric modulators, although its dynamic behavior remains elusive.
Further exploration of G protein-coupled receptor structural pharmacology should be closely linked to addressing unresolved clinical challenges, ensuring that ongoing research efforts translate into improved therapeutic outcomes.
https://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(25)00043-4
