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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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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.
GPCRs are also called heptahelical,...
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G Protein-coupled Receptors01:15

G Protein-coupled Receptors

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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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GPCRs Regulate Adenylyl Cylase Activity01:09

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Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
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G-protein Coupled Receptors01:21

G-protein Coupled Receptors

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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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GPCR Desensitization01:12

GPCR Desensitization

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G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
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Related Experiment Video

Updated: Sep 7, 2025

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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Activation and Speciation Mechanisms in Class A GPCRs.

Bentley Wingert1, Pemra Doruker1, Ivet Bahar1

  • 1Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.

Journal of Molecular Biology
|June 21, 2022
PubMed
Summary

Understanding G protein-coupled receptors (GPCRs) dynamics is crucial for developing allosteric modulators. This study reveals key structural and dynamic features differentiating GPCR subfamilies and species.

Keywords:
G-protein coupled receptorsconformational landscapeelastic network modelprincipal component analysissignature dynamics

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Last Updated: Sep 7, 2025

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Pharmacology

Background:

  • Allosteric modulators of G protein-coupled receptors (GPCRs) require deep understanding of their sequence, structure, and dynamics.
  • Recent advances in protein dynamics characterization provide new tools for GPCR analysis.

Purpose of the Study:

  • To analyze sequence similarities, structural landscape, and dynamic features of 160 Class A GPCRs across species, activation states, and subfamilies.
  • To elucidate the mechanisms of action and dynamic features distinguishing GPCR family members and subfamilies.

Main Methods:

  • Principal component analysis (PCA) of experimentally resolved GPCR structures.
  • Analysis of sequence similarities, structural landscape, and dynamic features.
  • Comparison across species (human, bovine, mouse, squid, rat), activation states (active/inactive), and subfamilies.

Main Results:

  • Identified two dominant directions of variability in GPCR structures, explaining cooperative activation, subfamily differentiation, and speciation.
  • Highlighted the functional significance of conformational flexibilities in specific structural elements like ICL3, TM5, TM6, and ECL2.
  • Demonstrated distinct conformational dynamics between active and inactive GPCR states, with robust dynamics in the active state and broad variance in inactive conformers.

Conclusions:

  • The study provides insights into the allosteric activation mechanisms and ligand-binding specificities of Class A GPCRs.
  • Understanding GPCR dynamics is essential for the accurate development of allosteric modulators.
  • Active and inactive GPCR states exhibit fundamentally different dynamic behaviors.