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Related Concept Videos

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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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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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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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Activation and Inactivation of G Proteins01:22

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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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G-Protein Gated Ion Channels01:21

G-Protein Gated Ion Channels

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GPCRs are primarily responsible for our sense of smell, taste, and vision.  The binding of a sensory stimulus activates GPCR to stimulate effector proteins, many of which are ion channels in the sensory organs. GPCRs modulate the opening and closing of the target ion channels either directly by binding them, or by releasing second messengers that activate these channels. As ions move across the membrane, the membrane potential is altered, which induces an appropriate response.
Sensory...
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Updated: Nov 12, 2025

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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Allosteric communication regulates ligand-specific GPCR activity.

Ning Ma1, Anita K Nivedha1, Nagarajan Vaidehi1

  • 1Department of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte, CA, USA.

The FEBS Journal
|March 19, 2021
PubMed
Summary
This summary is machine-generated.

G protein-coupled receptors (GPCRs) exhibit dynamic conformational states, enabling allosteric communication. Computational methods reveal conserved mechanisms for G protein coupling and guide the design of selective ligands and GPCR mutants.

Keywords:
AllosteerGPCRsallosteric communicationligand efficacymolecular dynamics

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Area of Science:

  • Biochemistry and Molecular Pharmacology
  • Computational Biology and Biophysics

Background:

  • G protein-coupled receptors (GPCRs) are crucial membrane proteins involved in diverse signaling pathways.
  • GPCRs exist in dynamic conformational equilibria, exhibiting basal activity and responding to ligand binding.
  • Ligand binding induces conformational shifts, modulating receptor activity through allosteric communication.

Purpose of the Study:

  • To review the current understanding of allosteric communication mechanisms in GPCRs.
  • To highlight the role of computational methods in elucidating these mechanisms.
  • To discuss the application of these insights in designing selective ligands and receptor mutants.

Main Methods:

  • Review of existing literature on GPCR allosteric communication.
  • Analysis of molecular dynamics simulations to identify key residues and pathways.
  • Structure-based drug design principles applied to GPCRs.

Main Results:

  • Identification of a conserved allosteric communication mechanism regulating G protein coupling.
  • Demonstration of computational methods for rational design of selective GPCR ligands.
  • Development of strategies for engineering GPCR mutants with altered ligand and/or G protein/β-arrestin selectivity.

Conclusions:

  • Computational approaches are vital for understanding GPCR allosteric communication.
  • Insights into allosteric mechanisms enable the design of targeted therapeutics.
  • Allosteric modulation offers a powerful strategy for fine-tuning GPCR signaling.