The activation of G protein-coupled receptors (GPCRs) is triggered by ligand binding to their orthosteric sites, which induces ligand-specific conformational changes. Agonists and antagonists bound to GPCR orthosteric sites provide detailed information on ligand-binding modes. Among these, peptide ligands play an instrumental role in GPCR pharmacology and have attracted increased attention as therapeutic drugs. The recent breakthrough in GPCR structural biology has resulted in the remarkable availability of peptide-bound GPCR complexes. Despite the several structural similarities shared by these receptors, they exhibit distinct features in terms of peptide recognition and receptor activation. From this perspective, we have summarized the current status of peptide-bound GPCR structural complexes, largely focusing on the interactions between the receptor and its peptide ligand at the orthosteric site. In-depth structural investigations have yielded valuable insights into the molecular mechanisms underlying peptide recognition. This study would contribute to the discovery of GPCR peptide drugs with improved therapeutic effects.

Glucocorticoid receptor (GR) regulates various cellular functions. Given its broad influence on metabolic activities, it has been the target of drug discovery for decades. However, how drugs induce conformational changes in GR has remained elusive. Herein, we used five GR agonists (dex, AZ938, pred, cor, and dibC) with different efficacies to investigate which aspect of the ligand induced the differences in efficacy. We performed molecular dynamics simulations on the five systems (dex-, AZ938-, pred-, cor-, and dibC-bound systems) and observed a distinct discrepancy in the conformation of the cofactor TIF2. Moreover, we discovered ligand-induced differences regarding the level of conformational changes posed by the binding of cofactor TIF2 and identified a pair of essential residues D590 and T39. We further found a positive correlation between the efficacies of ligands and the interaction of the two binding pockets’ domains, where D590 and T739 were involved, implying their significance in the participation of allosteric communication. Using community network analysis, two essential communities containing D590 and T739 were identified with their connectivity correlating to the efficacy of ligands. The potential communication pathways between these two residues were revealed. These results revealed the underlying mechanism of allosteric communication between the ligand-binding and cofactor-binding pockets and identified a pair of important residues in the allosteric communication pathway, which can serve as a guide for future drug discovery.

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