Allosteric Sites and Allosteric Regulators of G-Protein-Coupled Receptors: Gray Cardinals of Signal Transduction

Abstract

Membrane G protein-coupled receptors (GPCRs) are key components of most eukaryotic signaling systems, transducing external signals to intracellular effector proteins. Activation of GPCRs occurs through the specific binding of ligands of different nature to their orthosteric site. However, regulation of the affinity of an orthosteric agonist for the receptor, control of its effectiveness, and selection of the preferentially activated intracellular signaling cascade is carried out using allosteric mechanisms. This is due to the presence in GPCRs of many allosteric sites, which differ in structural and functional organization and topology in the receptor molecule, and are located in all its functional subdomains. The endogenous regulators of these sites are simple ions (Na+, Zn2+, Mg2+, Ca2+, Cl– and others), lipids (cholesterol, phospholipids, steroids), amino acids and their derivatives, polypeptides, as well as signaling proteins that form functionally active complexes with GPCRs (G proteins, β‑arrestins, RAMPs), and autoantibodies to the extracellular regions of GPCRs. Based on pharmacological activity, ligands of allosteric sites of GPCRs are divided into positive, negative or silent modulators of the effects of orthosteric agonists, as well as full and inverse agonists or neutral antagonists, which affect the basal activity of the receptor in the absence of an orthosteric agonist, although combining the properties of a modulator and an agonist is also possible. The multiplicity of allosteric sites and allosteric regulators, complex interactions between them, and the involvement of allosteric mechanisms in the formation of receptor complexes play a key role in fine-tuning the functional activity of signaling cascades, in biased agonism, and predetermine the processes of receptor desensitization and the fate of the receptor complex after hormonal signal transduction. The review summarizes and analyzes current concepts and new trends in the field of studying the allosteric regulation of GPCRs, the localization and functional role of allosteric sites, and their endogenous and synthetic ligands. As an example, synthetic allosteric regulators of the receptors of thyroid-stimulating and luteinizing hormones, as potential drugs for the correction of endocrine disorders, are discussed in detail.