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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
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A universal allosteric mechanism for G protein activation
Kevin M Knight1, Soumadwip Ghosh2, Sharon L Campbell3
1Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Molecular Cell
|February 26, 2021
Summary
Researchers identified a conserved G-R-E motif crucial for G protein subunit dissociation. This finding clarifies the final step in G protein activation, impacting signal transduction and pharmacology.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- G proteins are key regulators of cellular signal transduction.
- G protein activation involves receptor-mediated guanosine triphosphate (GTP) binding and subunit dissociation.
- The mechanism of G protein subunit dissociation remains poorly understood.
Purpose of the Study:
- To elucidate the molecular mechanism governing G protein subunit dissociation.
- To identify key molecular players involved in the release of Gα and Gβγ subunits.
Main Methods:
- Cell signaling assays
- Molecular dynamics (MD) simulations
- Biochemical analyses
- Structural analyses
Main Results:
- A conserved network of amino acids, termed the "G-R-E motif" (glycine, arginine, glutamate), was identified.
- This motif stabilizes GTP binding and allosterically promotes Gβγ dimer release.
- Mutations in the G-R-E motif abolish subunit dissociation, irrespective of GTP or agonist binding.
Conclusions:
- The G-R-E motif is essential for the final, committed step of G protein activation.
- Understanding this mechanism provides insights into G protein signaling and potential pharmacological targets.
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