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Rapid CommunicationMinireview—Special Section on Highlights from IUPHAR

Advances in G Protein-Coupled Receptor Allostery: From Function to Structure

Arthur Christopoulos
Molecular Pharmacology November 2014, 86 (5) 463-478; DOI: https://doi.org/10.1124/mol.114.094342
Arthur Christopoulos
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia
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Abstract

It is now widely accepted that G protein-coupled receptors (GPCRs) are highly dynamic proteins that adopt multiple active states linked to distinct functional outcomes. Furthermore, these states can be differentially stabilized not only by orthosteric ligands but also by allosteric ligands acting at spatially distinct binding sites. The key pharmacologic characteristics of GPCR allostery include improved selectivity due to either greater sequence divergence between receptor subtypes and/or subtype-selective cooperativity, a ceiling level to the effect, probe dependence (whereby the magnitude and direction of the allosteric effect change with the nature of the interacting ligands), and the potential for biased signaling. Recent chemical biology developments are beginning to demonstrate how the incorporation of analytical pharmacology and operational modeling into the experimental workflow can enrich structure-activity studies of allostery and bias, and have also led to the discovery of a new class of hybrid orthosteric/allosteric (bitopic) molecules. The potential for endogenous allosteric modulators to play a role in physiology and disease remains to be fully appreciated but will likely represent an important area for future studies. Finally, breakthroughs in structural and computational biology are beginning to unravel the mechanistic basis of GPCR allosteric modulation at the molecular level.

Footnotes

    • Received June 21, 2014.
    • Accepted July 24, 2014.
  • Portions of the work from the author’s laboratory were funded by the National Health and Medical Research Council of Australia (NHMRC) [Program Grant APP1055134 and Project Grant APP102696]. The author is a Principal Research Fellow of the NHMRC.

  • dx.doi.org/10.1124/mol.114.094342.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 86 (5)
Molecular Pharmacology
Vol. 86, Issue 5
1 Nov 2014
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Rapid CommunicationMinireview—Special Section on Highlights from IUPHAR

Advances in GPCR Allostery

Arthur Christopoulos
Molecular Pharmacology November 1, 2014, 86 (5) 463-478; DOI: https://doi.org/10.1124/mol.114.094342

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Rapid CommunicationMinireview—Special Section on Highlights from IUPHAR

Advances in GPCR Allostery

Arthur Christopoulos
Molecular Pharmacology November 1, 2014, 86 (5) 463-478; DOI: https://doi.org/10.1124/mol.114.094342
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  • Article
    • Abstract
    • Introduction
    • Classification of Allosteric Modulators
    • Pharmacologic Characteristics of GPCR Allostery
    • Enriching Structure-Activity Studies of GPCR Allostery and Bias
    • Bitopic GPCR Ligands
    • Endogenous Allosteric Modulators
    • Understanding the Structural Basis of GPCR Allostery
    • Concluding Remarks
    • Acknowledgments
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