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Allosteric modulation of G protein-coupled receptor signaling

G protein-coupled receptors (GPCRs), the largest family of transmembrane proteins, regulate a wide array of physiological processes in response to extracellular signals. Although these receptors have proven to be the most successful class of drug targets, their complicated signal transduction pathwa...

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Autores principales: Shen, Siyuan, Zhao, Chang, Wu, Chao, Sun, Suyue, Li, Ziyan, Yan, Wei, Shao, Zhenhua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9978769/
https://www.ncbi.nlm.nih.gov/pubmed/36875468
http://dx.doi.org/10.3389/fendo.2023.1137604
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author Shen, Siyuan
Zhao, Chang
Wu, Chao
Sun, Suyue
Li, Ziyan
Yan, Wei
Shao, Zhenhua
author_facet Shen, Siyuan
Zhao, Chang
Wu, Chao
Sun, Suyue
Li, Ziyan
Yan, Wei
Shao, Zhenhua
author_sort Shen, Siyuan
collection PubMed
description G protein-coupled receptors (GPCRs), the largest family of transmembrane proteins, regulate a wide array of physiological processes in response to extracellular signals. Although these receptors have proven to be the most successful class of drug targets, their complicated signal transduction pathways (including different effector G proteins and β-arrestins) and mediation by orthosteric ligands often cause difficulties for drug development, such as on- or off-target effects. Interestingly, identification of ligands that engage allosteric binding sites, which are different from classic orthosteric sites, can promote pathway-specific effects in cooperation with orthosteric ligands. Such pharmacological properties of allosteric modulators offer new strategies to design safer GPCR-targeted therapeutics for various diseases. Here, we explore recent structural studies of GPCRs bound to allosteric modulators. Our inspection of all GPCR families reveals recognition mechanisms of allosteric regulation. More importantly, this review highlights the diversity of allosteric sites and presents how allosteric modulators control specific GPCR pathways to provide opportunities for the development of new valuable agents.
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spelling pubmed-99787692023-03-03 Allosteric modulation of G protein-coupled receptor signaling Shen, Siyuan Zhao, Chang Wu, Chao Sun, Suyue Li, Ziyan Yan, Wei Shao, Zhenhua Front Endocrinol (Lausanne) Endocrinology G protein-coupled receptors (GPCRs), the largest family of transmembrane proteins, regulate a wide array of physiological processes in response to extracellular signals. Although these receptors have proven to be the most successful class of drug targets, their complicated signal transduction pathways (including different effector G proteins and β-arrestins) and mediation by orthosteric ligands often cause difficulties for drug development, such as on- or off-target effects. Interestingly, identification of ligands that engage allosteric binding sites, which are different from classic orthosteric sites, can promote pathway-specific effects in cooperation with orthosteric ligands. Such pharmacological properties of allosteric modulators offer new strategies to design safer GPCR-targeted therapeutics for various diseases. Here, we explore recent structural studies of GPCRs bound to allosteric modulators. Our inspection of all GPCR families reveals recognition mechanisms of allosteric regulation. More importantly, this review highlights the diversity of allosteric sites and presents how allosteric modulators control specific GPCR pathways to provide opportunities for the development of new valuable agents. Frontiers Media S.A. 2023-02-16 /pmc/articles/PMC9978769/ /pubmed/36875468 http://dx.doi.org/10.3389/fendo.2023.1137604 Text en Copyright © 2023 Shen, Zhao, Wu, Sun, Li, Yan and Shao https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Shen, Siyuan
Zhao, Chang
Wu, Chao
Sun, Suyue
Li, Ziyan
Yan, Wei
Shao, Zhenhua
Allosteric modulation of G protein-coupled receptor signaling
title Allosteric modulation of G protein-coupled receptor signaling
title_full Allosteric modulation of G protein-coupled receptor signaling
title_fullStr Allosteric modulation of G protein-coupled receptor signaling
title_full_unstemmed Allosteric modulation of G protein-coupled receptor signaling
title_short Allosteric modulation of G protein-coupled receptor signaling
title_sort allosteric modulation of g protein-coupled receptor signaling
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9978769/
https://www.ncbi.nlm.nih.gov/pubmed/36875468
http://dx.doi.org/10.3389/fendo.2023.1137604
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