Structural Insights into Ligand—Receptor Interactions Involved in Biased Agonism of G-Protein Coupled Receptors

Abstract

G protein-coupled receptors (GPCRs) are versatile signaling proteins that mediate complex cellular responses to hormones and neurotransmitters. Ligand directed signaling is observed when agonists, upon binding to the same receptor, trigger significantly different configuration of intracellular events. The current work reviews the structurally defined ligand – receptor interactions that can be related to specific molecular mechanisms of ligand directed signaling across different receptors belonging to class A of GPCRs. Recent advances in GPCR structural biology allow for mapping receptors’ binding sites with residues particularly important in recognition of ligands’ structural features that are responsible for biased signaling. Various studies show particular role of specific residues lining the extended ligand binding domains, biased agonists may alternatively affect their interhelical interactions and flexibility what can be translated into intracellular loop rearrangements. Studies on opioid and angiotensin receptors indicate importance of residues located deeper within the binding cavity and direct interactions with receptor residues linking the ortosteric ligand binding site with the intracellular transducer binding domain. Collection of results across different receptors may suggest elements of common molecular mechanisms which are responsible for passing alternative signals from biased agonists.

Biased signaling due to oligomerization of the G protein-coupled platelet-activating factor receptor

“…Among other possibilities 11,71,72 , distinct GPCR conformations stabilized by biased ligands and likely with different affinities for G proteins and arrestins were proposed to activate one or another signaling cascade. This has also been demonstrated through a structural analysis of class A GPCRs where residues interacting specifically with biased ligands were identified [73][74][75] . These residues are often those that form the agonist-binding pocket and are involved in interhelical interactions as well.…”

“…These residues are often those that form the agonist-binding pocket and are involved in interhelical interactions as well. Biased ligands induce slightly different positions in the intracellular part of TMs, in particular TM5, TM6, and TM7 28,73,75 . Since TM5 is often involved in dimer formation, its positioning may be affected by dimerization.…”

The Implication of 5-HT Receptor Family Members in Aggression, Depression and Suicide: Similarity and Difference

“…Additionally, for these receptor subtypes, biased agonism was demonstrated. This phenomenon results in activation of different signal pathways depending on ligand [ 24 , 264 , 265 , 266 ]. At the same time, for 5-HT 2C receptors, mRNA-editing resulting in the translation of various isoforms of receptor was shown [ 267 , 268 , 269 ].…”

Biased Signaling in Mutated Variants of β2-Adrenergic Receptor: Insights from Molecular Dynamics Simulations

“…We observe alterations in agonist interaction energy for several orthosteric pocket residues in B2RY and B2RTYY (Figures S13a,b), and this clearly establishes the allosteric perturbations at the distal extracellular regions induced by transducer-selective mutations. We note that previous experimental and MD simulation studies have highlighted the role of extracellular agonist-binding residues in modulating the biased signaling in GPCRs. − …”