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.
Highlights
Structural results led to the postulate that L1123.36 and Y2927.43 residues of Angiotensin receptor 1 (AT1) played a decisive role in inducing the receptor coupling to Gq protein upon binding of angiotensin II (AngII)
The hypothesis was validated by extensive molecular dynamics simulations of the AngII–AT1 complex [59]
The simulations suggested that the agonist bound receptor was oscillating between two conformations referred to as canonical active conformation or alternative active conformation
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Both the bucindolol and carvedilol bound complexes did not exhibit the contraction of the binding pocket characteristic for the structures with full and partial agonist bound, an indication that these two ligands did not induce the initial conformational changes in the receptor needed to activate G proteins [21]. Their bulky aromatic moieties at the aminoalkyl end occupied the so-called extended ligand binding domain (ELBD), the space between the upper part of TM6 and TM7 capped by the extracellular loop 2 (ECL2). PEER REVIEW and inducing [Gs + Gi ] signaling pattern, Figure 1B, where Y3087.35 residue forms alternative interhelical HB with nearby N2936.55 residue
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