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Related Experiment Videos

G protein-coupled receptor allosterism and complexing.

Arthur Christopoulos1, Terry Kenakin

  • 1Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia. arthurc1@unimelb.edu.au

Pharmacological Reviews
|May 31, 2002
PubMed
Summary

G protein-coupled receptors (GPCRs) are allosteric proteins. Understanding allosteric modulation of GPCRs offers new drug discovery avenues with improved selectivity and safety.

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Area of Science:

  • Pharmacology
  • Molecular Biology
  • Biochemistry

Background:

  • G protein-coupled receptors (GPCRs) are the largest cell-surface receptor family.
  • GPCRs function as allosteric proteins, involving conformational changes between agonist and G protein binding sites.
  • Agonist-bound GPCRs can form ternary complexes with other molecules, altering signaling.

Purpose of the Study:

  • To review allosteric receptor models for GPCRs.
  • To discuss the detection and quantification of allosteric effects.
  • To explore potential allosteric sites, modulators, and the role of GPCR oligomerization and accessory proteins.

Main Methods:

  • Review of existing literature on GPCR allosteric modulation.
  • Discussion of equilibrium binding, nonequilibrium kinetic, and functional signaling assays.
  • Analysis of GPCR structure, function, and drug discovery implications.

Main Results:

  • Allosteric sites on GPCRs are novel drug targets with theoretical advantages over orthosteric ligands.
  • Allosteric modulators offer potential for ceiling effects and enhanced subtype-selectivity.
  • Allosteric effects can arise from GPCR oligomerization or complex formation with accessory proteins.

Conclusions:

  • Allosteric modulation of GPCRs presents significant opportunities for drug discovery.
  • Further research into GPCR allosteric mechanisms is crucial for developing targeted therapeutics.
  • Advancements in GPCR screening technologies will increase the importance of studying allosteric phenomena.

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