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Related Concept Videos

Transducer Mechanism: G Protein–Coupled Receptors01:30

Transducer Mechanism: G Protein–Coupled Receptors

4.0K
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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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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GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

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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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Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

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Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
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Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

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G Protein-coupled Receptors01:15

G Protein-coupled Receptors

16.5K
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.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
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Related Experiment Video

Updated: Jan 14, 2026

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators

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Designing allosteric modulators to change GPCR G protein subtype selectivity.

Madelyn N Moore1, Kelsey L Person1, Valeria L Robleto1

  • 1Department of Pharmacology, University of Minnesota Twin Cities, Minneapolis, MN, USA.

Nature
|October 22, 2025
PubMed
Summary
This summary is machine-generated.

Researchers developed biased compounds that selectively target G-protein-coupled receptors (GPCRs) by modifying small molecules. This approach enables tailored drug discovery for safer and more effective medications by controlling G protein signaling pathways.

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G Protein-selective GPCR Conformations Measured Using FRET Sensors in a Live Cell Suspension Fluorometer Assay
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Genetically-encoded Molecular Probes to Study G Protein-coupled Receptors
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Related Experiment Videos

Last Updated: Jan 14, 2026

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
07:41

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators

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G Protein-selective GPCR Conformations Measured Using FRET Sensors in a Live Cell Suspension Fluorometer Assay
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G Protein-selective GPCR Conformations Measured Using FRET Sensors in a Live Cell Suspension Fluorometer Assay

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Genetically-encoded Molecular Probes to Study G Protein-coupled Receptors
16:16

Genetically-encoded Molecular Probes to Study G Protein-coupled Receptors

Published on: September 13, 2013

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Area of Science:

  • Pharmacology
  • Molecular Biology
  • Drug Discovery

Background:

  • G-protein-coupled receptors (GPCRs) mediate cellular responses to extracellular signals via G proteins and β-arrestins.
  • Biased compounds offer potential for safer, more effective therapeutics by selectively activating specific signaling pathways.
  • Understanding the determinants of GPCR bias is crucial for rational drug design.

Purpose of the Study:

  • To investigate how small molecules binding to the intracellular GPCR-transducer interface influence G protein coupling specificity.
  • To enable structure-guided design of biased GPCR modulators with tailored G protein selectivity.

Main Methods:

  • Utilized the neurotensin receptor 1 (NTSR1) as a model class A GPCR.
  • Employed small molecule SBI-553 and its derivatives to probe the intracellular receptor-transducer interface.
  • Assessed G protein coupling selectivity and in vivo activity of developed allosteric modulators.

Main Results:

  • Demonstrated that intracellular small molecules can predictably alter GPCR G protein coupling in a subtype-specific manner.
  • SBI-553 was shown to switch NTSR1's G protein preference through direct interactions at the transducer interface.
  • Modified scaffolds yielded allosteric modulators with distinct, probe-independent, and species-conserved G protein selectivity profiles.

Conclusions:

  • GPCR G protein selectivity can be precisely tuned by small chemical modifications targeting the receptor-transducer interface.
  • This strategy holds promise for developing pathway-selective drugs across the broad GPCR superfamily due to conserved binding pockets.