A kinetic view of GPCR allostery and biased agonism

J Robert Lane, Lauren T May, Robert G Parton, Patrick M. Sexton, Arthur Christopoulos

Research output: Contribution to journalReview ArticleResearchpeer-review

Abstract

G-protein-coupled receptors (GPCRs) are one of the most tractable classes of drug targets. These dynamic proteins can adopt multiple active states that are linked to distinct functional outcomes. Such states can be differentially stabilized by ligands interacting with the endogenous agonist-binding orthosteric site and/or by ligands acting via spatially distinct allosteric sites, leading to the phenomena of 'biased agonism' or 'biased modulation'. These paradigms are having a major impact on modern drug discovery, but it is becoming increasingly apparent that 'kinetic context', at the level of both ligand-receptor and receptor-signal pathway kinetics, can have a profound impact on the observation and quantification of these phenomena. The concept of kinetic context thus represents an important new consideration that should be routinely incorporated into contemporary chemical biology and drug discovery studies of GPCR bias and allostery.

Original languageEnglish
Pages (from-to)929-937
Number of pages9
JournalNature Chemical Biology
Volume13
Issue number9
DOIs
Publication statusPublished - 18 Aug 2017

Cite this

@article{d41c099bd86b457c91327c164a943d50,
title = "A kinetic view of GPCR allostery and biased agonism",
abstract = "G-protein-coupled receptors (GPCRs) are one of the most tractable classes of drug targets. These dynamic proteins can adopt multiple active states that are linked to distinct functional outcomes. Such states can be differentially stabilized by ligands interacting with the endogenous agonist-binding orthosteric site and/or by ligands acting via spatially distinct allosteric sites, leading to the phenomena of 'biased agonism' or 'biased modulation'. These paradigms are having a major impact on modern drug discovery, but it is becoming increasingly apparent that 'kinetic context', at the level of both ligand-receptor and receptor-signal pathway kinetics, can have a profound impact on the observation and quantification of these phenomena. The concept of kinetic context thus represents an important new consideration that should be routinely incorporated into contemporary chemical biology and drug discovery studies of GPCR bias and allostery.",
author = "Lane, {J Robert} and May, {Lauren T} and Parton, {Robert G} and Sexton, {Patrick M.} and Arthur Christopoulos",
year = "2017",
month = "8",
day = "18",
doi = "10.1038/nchembio.2431",
language = "English",
volume = "13",
pages = "929--937",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "Nature Publishing Group",
number = "9",

}

A kinetic view of GPCR allostery and biased agonism. / Lane, J Robert; May, Lauren T; Parton, Robert G; Sexton, Patrick M.; Christopoulos, Arthur.

In: Nature Chemical Biology, Vol. 13, No. 9, 18.08.2017, p. 929-937.

Research output: Contribution to journalReview ArticleResearchpeer-review

TY - JOUR

T1 - A kinetic view of GPCR allostery and biased agonism

AU - Lane, J Robert

AU - May, Lauren T

AU - Parton, Robert G

AU - Sexton, Patrick M.

AU - Christopoulos, Arthur

PY - 2017/8/18

Y1 - 2017/8/18

N2 - G-protein-coupled receptors (GPCRs) are one of the most tractable classes of drug targets. These dynamic proteins can adopt multiple active states that are linked to distinct functional outcomes. Such states can be differentially stabilized by ligands interacting with the endogenous agonist-binding orthosteric site and/or by ligands acting via spatially distinct allosteric sites, leading to the phenomena of 'biased agonism' or 'biased modulation'. These paradigms are having a major impact on modern drug discovery, but it is becoming increasingly apparent that 'kinetic context', at the level of both ligand-receptor and receptor-signal pathway kinetics, can have a profound impact on the observation and quantification of these phenomena. The concept of kinetic context thus represents an important new consideration that should be routinely incorporated into contemporary chemical biology and drug discovery studies of GPCR bias and allostery.

AB - G-protein-coupled receptors (GPCRs) are one of the most tractable classes of drug targets. These dynamic proteins can adopt multiple active states that are linked to distinct functional outcomes. Such states can be differentially stabilized by ligands interacting with the endogenous agonist-binding orthosteric site and/or by ligands acting via spatially distinct allosteric sites, leading to the phenomena of 'biased agonism' or 'biased modulation'. These paradigms are having a major impact on modern drug discovery, but it is becoming increasingly apparent that 'kinetic context', at the level of both ligand-receptor and receptor-signal pathway kinetics, can have a profound impact on the observation and quantification of these phenomena. The concept of kinetic context thus represents an important new consideration that should be routinely incorporated into contemporary chemical biology and drug discovery studies of GPCR bias and allostery.

UR - http://www.scopus.com/inward/record.url?scp=85027834609&partnerID=8YFLogxK

U2 - 10.1038/nchembio.2431

DO - 10.1038/nchembio.2431

M3 - Review Article

VL - 13

SP - 929

EP - 937

JO - Nature Chemical Biology

JF - Nature Chemical Biology

SN - 1552-4450

IS - 9

ER -