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Advances in G protein-coupled receptor allostery: from function to structure
1Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia arthur.christopoulos@monash.edu.
Molecular Pharmacology
|July 26, 2014
Summary
G protein-coupled receptors (GPCRs) are dynamic proteins with multiple active states. Allosteric ligands offer improved selectivity and biased signaling potential, advancing drug discovery.
Area of Science:
- Pharmacology
- Biochemistry
- Structural Biology
Background:
- G protein-coupled receptors (GPCRs) are recognized as highly dynamic proteins.
- GPCRs adopt multiple active states influencing distinct functional outcomes.
- Ligands, both orthosteric and allosteric, can stabilize these distinct GPCR states.
Purpose of the Study:
- To review the pharmacological characteristics of GPCR allostery.
- To highlight recent advances in chemical biology and their impact on studying GPCR allosteric modulation.
- To discuss the potential of GPCR allosteric modulators in physiology and disease.
Main Methods:
- Review of chemical biology developments.
- Incorporation of analytical pharmacology and operational modeling.
- Advances in structural and computational biology.
Main Results:
- GPCR allostery exhibits key characteristics: improved selectivity, ceiling effects, probe dependence, and biased signaling.
- New hybrid orthosteric/allosteric (bitopic) molecules have been discovered.
- Mechanistic insights into GPCR allosteric modulation are emerging from structural and computational studies.
Conclusions:
- GPCR allosteric modulation is a complex phenomenon with significant therapeutic potential.
- Future research will likely focus on the role of endogenous allosteric modulators in health and disease.
- Understanding the molecular basis of GPCR allostery is crucial for drug development.
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