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Related Concept Videos

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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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 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.
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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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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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Unraveling GPCRs Allosteric Modulation. Cannabinoid 1 Receptor as a Case Study.

Alejandro Cruz1, Arieh Warshel1

  • 1Department of Chemistry, University of Southern California, Los Angeles, California, USA.

Proteins
|November 25, 2024
PubMed
Summary

This study reveals how positive allosteric modulators interact with the Cannabinoid type-1 receptor (CB1R). The research identified key molecular mechanisms and residues involved in CB1R allosteric modulation, offering insights for drug development.

Keywords:
GPCRs allosteric modulationbinding free energy calculationscannabinoid type‐1 receptorcannabinoid type‐1 receptor positive allosteric modulationcooperativity factordissociation constantfolding free energy calculations

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Area of Science:

  • Biophysics
  • Computational Chemistry
  • Pharmacology

Background:

  • G-protein-coupled receptors (GPCRs) are crucial for cell signaling and are targets for treating diseases like Parkinson's.
  • Traditional orthosteric ligands for GPCRs can cause side effects due to cross-reactivity with similar receptors.
  • Allosteric modulation offers a more selective therapeutic approach, necessitating detailed molecular understanding.

Purpose of the Study:

  • To investigate the molecular mechanisms of positive allosteric modulation at the Cannabinoid type-1 receptor (CB1R).
  • To evaluate the binding affinities and cooperativity of 2-phenylindole derivatives as CB1R positive allosteric modulators.
  • To identify key residues and structural changes involved in CB1R allosteric modulation.

Main Methods:

  • Utilized a coarse-grained (CG) model of membrane proteins combined with the protein-dipole Langevin-dipole (PDLD/S-2000) method.
  • Evaluated dissociation constants (KBs) and cooperativity factors (αs) for CB1R allosteric modulators.
  • Analyzed the structural complexes of allosteric modulators with CB1R and the agonist CP55940.

Main Results:

  • Successfully identified and characterized populated allosteric modulator:CB1R and modulator:agonist:CB1R complexes.
  • Determined that CB1R positive allosteric modulation involves outward displacement of TM4 and regulation of TM7 movement.
  • Identified Lys1923.28 and Gly1943.30 as critical residues for electrostatic interactions in the allosteric site.

Conclusions:

  • The study provides a detailed molecular understanding of CB1R positive allosteric modulation.
  • The findings rationalize structure-activity relationships and stereoselectivity of 2-phenylindole modulators.
  • The employed computational methodology demonstrates predictive value for other biophysical systems and GPCR research.