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Related Concept Videos

Activation and Inactivation of G Proteins01:22

Activation and Inactivation of G Proteins

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Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
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GTPases and their Regulation02:14

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Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒  small G-proteins consisting of a single domain and large multi-domain G-proteins.
Large G-proteins,...
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Transducer Mechanism: G Protein–Coupled Receptors01:30

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G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
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G Protein-coupled Receptors01:15

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G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
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G-protein Coupled Receptors01:21

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G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
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Amplifying Signals via Enzymatic Cascade01:22

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When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
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Updated: Jun 29, 2025

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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G Protein Activation Occurs via a Largely Universal Mechanism.

Neha Vithani1,2, Tyson D Todd3, Sukrit Singh1,2

  • 1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States.

The Journal of Physical Chemistry. B
|April 5, 2024
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Summary

Computer simulations reveal conserved allosteric networks in G protein alpha subunits. Pathway-I dominates over Pathway-II, impacting nucleotide exchange and offering potential for isoform-specific drug design.

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Area of Science:

  • Molecular Biology
  • Biophysics
  • Computational Biology

Background:

  • Allosteric activation of signaling proteins like G proteins is crucial but challenging to study due to dynamic processes.
  • Current understanding relies on static structures, mutagenesis, and sequence conservation, limiting direct observation.

Purpose of the Study:

  • To directly investigate allosteric coupling in G protein alpha subunits using computer simulations.
  • To develop and apply automated methods for inferring and comparing allosteric networks across isoforms.

Main Methods:

  • Utilized extensive computer simulations to analyze allosteric coupling in six G protein alpha subunit isoforms.
  • Developed automated methods to infer allosteric networks from simulation data.
  • Assessed conservation and divergence of allosteric pathways among related isoforms.
  • Performed experimental validation through mutagenesis studies on key allosteric pathways.

Main Results:

  • Identified largely conserved allosteric networks across the studied G protein alpha subunits.
  • Discovered two dominant allosteric pathways, termed pathway-I and pathway-II.
  • Demonstrated experimental evidence that pathway-I is generally dominant over pathway-II in regulating nucleotide exchange.

Conclusions:

  • Allosteric networks in G protein alpha subunits are highly conserved, primarily utilizing pathway-I and pathway-II.
  • Pathway-I plays a more significant role in modulating nucleotide exchange compared to pathway-II.
  • The developed computational tools can advance the study of allostery in G proteins and other proteins, potentially guiding the development of targeted therapeutics.