Biased agonism in peptide-GPCRs: A structural perspective.

Abstract

G protein-coupled receptors (GPCRs) are dynamic membrane receptors that transduce extracellular signals to the cell interior via a ligand-receptor-effector (ternary) complex that functions via allosterism. Among many signalling molecules, peptides constitute an important class of primary messengers that interact with their cognate GPCRs (peptide-GPCRs). Compared to small-molecule analogues, peptides are more potent and selective at their targets. "Biased agonism", a therapeutically relevant phenomenon exhibited by GPCRs owing to their allosteric nature, has also been observed in peptide-GPCRs, leading to the development of selective therapeutics with fewer side effects. In this review, we have focused on the structural basis of bias by comparing the interactions of biased and balanced peptide ligands at the orthosteric ligand binding sites of peptide-GPCRs of classes A and B, and reviewed the therapeutic relevance of bias at peptide-GPCRs, with the hope of contributing to the discovery of novel biased peptide drugs.