Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

Abstract

Allosteric regulation is critical for the functioning of G protein-coupled receptors (GPCRs) and their signaling pathways. Endogenous allosteric regulators of GPCRs are simple ions, various biomolecules, and protein components of GPCR signaling (G proteins and β-arrestins). The stability and functional activity of GPCR complexes is also due to multicenter allosteric interactions between protomers. The complexity of allosteric effects caused by numerous regulators differing in structure, availability, and mechanisms of action predetermines the multiplicity and different topology of allosteric sites in GPCRs. These sites can be localized in extracellular loops; inside the transmembrane tunnel and in its upper and lower vestibules; in cytoplasmic loops; and on the outer, membrane-contacting surface of the transmembrane domain. They are involved in the regulation of basal and orthosteric agonist-stimulated receptor activity, biased agonism, GPCR-complex formation, and endocytosis. They are targets for a large number of synthetic allosteric regulators and modulators, including those constructed using molecular docking. The review is devoted to the principles and mechanisms of GPCRs allosteric regulation, the multiplicity of allosteric sites and their topology, and the endogenous and synthetic allosteric regulators, including autoantibodies and pepducins. The allosteric regulation of chemokine receptors, proteinase-activated receptors, thyroid-stimulating and luteinizing hormone receptors, and beta-adrenergic receptors are described in more detail.

Expanding the ligandable proteome by paralog hopping with covalent probes

“…Finally, the different functional effects displayed by 2,6-diazaspiro [3.4]octane and tryptoline acrylamide ligands targeting N112C-CCNE1 -inhibition of CDK2 and stabilization of CKS1B/CKS2 interactions, respectively -underscore the potential for allosteric sites to modulate distinct biochemical activities of proteins [67][68][69] . While we do not yet understand how promoting interactions with CKS1B/CKS2 may impact the function of CCNE1:CDK2 complexes, it is possible that tryptoline acrylamides displaying this property may function as substrateselective agonists in cells 45,46 .…”

Structural and dynamic insights into the activation of the μ-opioid receptor by an allosteric modulator

“…Interestingly, allosteric modulators, compounds that bind to receptor sites different from the orthosteric ligand-binding site, have been shown to enhance GPCR activation beyond what is achievable by orthosteric agonists alone 9 . Although there are examples that have studied the mechanism of allosteric modulation of GPCRs using in silico approaches 10 – 13 , the structural basis underlying the activity enhancement by the allosteric modulators remains incompletely understood. This gap in knowledge could potentially hinder the rational design of allosteric modulators.…”

Comparison of Steroidogenic and Ovulation-Inducing Effects of Orthosteric and Allosteric Agonists of Luteinizing Hormone/Chorionic Gonadotropin Receptor in Immature Female Rats

“…All of the above makes it necessary to search for alternative ways to induce ovulation, and great expectations are associated with the low-molecular-weight heterocyclic compounds with the properties of allosteric agonists of the LH/hCG receptor [14][15][16][17]. These compounds specifically interact with the allosteric site located within the transmembrane domain of the LH/hCG receptor, while LH and hCG bind with high affinity to the orthosteric site located in the large extracellular domain of the LH/hCG receptor.…”