Mechanisms of signalling and biased agonism in G protein-coupled receptors

Denise L Wootten, Arthur Christopoulos, Maria Marti-Solano, M. Madan Babu, Patrick M Sexton

Research output: Contribution to journalReview ArticleResearchpeer-review

Abstract

G protein-coupled receptors (GPCRs) are the largest group of cell surface receptors in humans that signal in response to diverse inputs and regulate a plethora of cellular processes. Hence, they constitute one of the primary drug target classes. Progress in our understanding of GPCR dynamics, activation and signalling has opened new possibilities for selective drug development. A key advancement has been provided by the concept of biased agonism, which describes the ability of ligands acting at the same GPCR to elicit distinct cellular signalling profiles by preferentially stabilizing different active conformational states of the receptor. Application of this concept raises the prospect of ‘designer’ biased agonists as optimized therapeutics with improved efficacy and/or reduced side-effect profiles. However, this application will require a detailed understanding of the spectrum of drug actions and a structural understanding of the drug–receptor interactions that drive distinct pharmacologies. The recent revolution in GPCR structural biology provides unprecedented insights into ligand binding, conformational dynamics and the control of signalling outcomes. These insights, together with new approaches to multi-dimensional analysis of drug action, are allowing refined classification of drugs according to their pharmacodynamic profiles, which can be linked to receptor structure and predictions of preclinical drug efficacy.

Original languageEnglish
Pages (from-to)638-653
Number of pages16
JournalNature Reviews Molecular Cell Biology
Volume19
Issue number10
DOIs
Publication statusPublished - Oct 2018

Cite this

@article{39728084416147e1809ac2b28a15f8e7,
title = "Mechanisms of signalling and biased agonism in G protein-coupled receptors",
abstract = "G protein-coupled receptors (GPCRs) are the largest group of cell surface receptors in humans that signal in response to diverse inputs and regulate a plethora of cellular processes. Hence, they constitute one of the primary drug target classes. Progress in our understanding of GPCR dynamics, activation and signalling has opened new possibilities for selective drug development. A key advancement has been provided by the concept of biased agonism, which describes the ability of ligands acting at the same GPCR to elicit distinct cellular signalling profiles by preferentially stabilizing different active conformational states of the receptor. Application of this concept raises the prospect of ‘designer’ biased agonists as optimized therapeutics with improved efficacy and/or reduced side-effect profiles. However, this application will require a detailed understanding of the spectrum of drug actions and a structural understanding of the drug–receptor interactions that drive distinct pharmacologies. The recent revolution in GPCR structural biology provides unprecedented insights into ligand binding, conformational dynamics and the control of signalling outcomes. These insights, together with new approaches to multi-dimensional analysis of drug action, are allowing refined classification of drugs according to their pharmacodynamic profiles, which can be linked to receptor structure and predictions of preclinical drug efficacy.",
author = "Wootten, {Denise L} and Arthur Christopoulos and Maria Marti-Solano and Babu, {M. Madan} and Sexton, {Patrick M}",
year = "2018",
month = "10",
doi = "10.1038/s41580-018-0049-3",
language = "English",
volume = "19",
pages = "638--653",
journal = "Nature Reviews Molecular Cell Biology",
issn = "1471-0072",
publisher = "Nature Research",
number = "10",

}

Mechanisms of signalling and biased agonism in G protein-coupled receptors. / Wootten, Denise L; Christopoulos, Arthur; Marti-Solano, Maria; Babu, M. Madan; Sexton, Patrick M.

In: Nature Reviews Molecular Cell Biology, Vol. 19, No. 10, 10.2018, p. 638-653.

Research output: Contribution to journalReview ArticleResearchpeer-review

TY - JOUR

T1 - Mechanisms of signalling and biased agonism in G protein-coupled receptors

AU - Wootten, Denise L

AU - Christopoulos, Arthur

AU - Marti-Solano, Maria

AU - Babu, M. Madan

AU - Sexton, Patrick M

PY - 2018/10

Y1 - 2018/10

N2 - G protein-coupled receptors (GPCRs) are the largest group of cell surface receptors in humans that signal in response to diverse inputs and regulate a plethora of cellular processes. Hence, they constitute one of the primary drug target classes. Progress in our understanding of GPCR dynamics, activation and signalling has opened new possibilities for selective drug development. A key advancement has been provided by the concept of biased agonism, which describes the ability of ligands acting at the same GPCR to elicit distinct cellular signalling profiles by preferentially stabilizing different active conformational states of the receptor. Application of this concept raises the prospect of ‘designer’ biased agonists as optimized therapeutics with improved efficacy and/or reduced side-effect profiles. However, this application will require a detailed understanding of the spectrum of drug actions and a structural understanding of the drug–receptor interactions that drive distinct pharmacologies. The recent revolution in GPCR structural biology provides unprecedented insights into ligand binding, conformational dynamics and the control of signalling outcomes. These insights, together with new approaches to multi-dimensional analysis of drug action, are allowing refined classification of drugs according to their pharmacodynamic profiles, which can be linked to receptor structure and predictions of preclinical drug efficacy.

AB - G protein-coupled receptors (GPCRs) are the largest group of cell surface receptors in humans that signal in response to diverse inputs and regulate a plethora of cellular processes. Hence, they constitute one of the primary drug target classes. Progress in our understanding of GPCR dynamics, activation and signalling has opened new possibilities for selective drug development. A key advancement has been provided by the concept of biased agonism, which describes the ability of ligands acting at the same GPCR to elicit distinct cellular signalling profiles by preferentially stabilizing different active conformational states of the receptor. Application of this concept raises the prospect of ‘designer’ biased agonists as optimized therapeutics with improved efficacy and/or reduced side-effect profiles. However, this application will require a detailed understanding of the spectrum of drug actions and a structural understanding of the drug–receptor interactions that drive distinct pharmacologies. The recent revolution in GPCR structural biology provides unprecedented insights into ligand binding, conformational dynamics and the control of signalling outcomes. These insights, together with new approaches to multi-dimensional analysis of drug action, are allowing refined classification of drugs according to their pharmacodynamic profiles, which can be linked to receptor structure and predictions of preclinical drug efficacy.

UR - http://www.scopus.com/inward/record.url?scp=85052494077&partnerID=8YFLogxK

U2 - 10.1038/s41580-018-0049-3

DO - 10.1038/s41580-018-0049-3

M3 - Review Article

VL - 19

SP - 638

EP - 653

JO - Nature Reviews Molecular Cell Biology

JF - Nature Reviews Molecular Cell Biology

SN - 1471-0072

IS - 10

ER -