Abstract
Recent advances in structural biology have profoundly enhanced our understanding of G protein-coupled receptors (GPCRs), providing detailed molecular insights into their activation and ligand recognition. Here, in this Review, we explore the molecular mechanisms of class A and class B GPCRs bound to peptide agonists and their implications for drug development. We examine representative GPCRs, such as the angiotensin II type 1 receptor, chemokine receptor 5, μ-opioid receptor, parathyroid hormone 1 receptor and glucagon-like peptide 1 receptor (GLP-1R), highlighting their activation processes upon peptide ligand binding. Comparative analysis of structures bound to endogenous and synthetic peptide ligands reveals critical insights for rational drug design. A case study on GLP-1R demonstrates how structural insights have led to the design of successful drugs for type 2 diabetes and obesity. This comparative structural analysis aims to deepen our understanding of GPCR activation mechanisms and support future drug discovery efforts targeting peptide-binding GPCRs.