Akinetic view of GPCR allostery and biased agonism

Lane, J. Robert, May, Lauren T., Parton, Robert G., Sexton, Patrick M. and Christopoulos, Arthur (2017) Akinetic view of GPCR allostery and biased agonism. Nature Chemical Biology, 13 9: 929-937. doi:10.1038/nchembio.2431

Author Lane, J. Robert
May, Lauren T.
Parton, Robert G.
Sexton, Patrick M.
Christopoulos, Arthur
Title Akinetic view of GPCR allostery and biased agonism
Journal name Nature Chemical Biology   Check publisher's open access policy
ISSN 1552-4469
Publication date 2017-08-18
Year available 2017
Sub-type Critical review of research, literature review, critical commentary
DOI 10.1038/nchembio.2431
Open Access Status Not yet assessed
Volume 13
Issue 9
Start page 929
End page 937
Total pages 9
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 1312 Molecular Biology
1307 Cell Biology
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.
Keyword Protein-Coupled Receptor
Muscarinic Acetylcholine-Receptor
Beta(2) Adrenergic-Receptor
Adenosine A(1) Receptor
Ternary Complex Model
Beta(2)-Adrenergic Receptor
Negative Cooperativity
Functional Selectivity
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 4 times in Thomson Reuters Web of Science Article | Citations
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