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Related Concept Videos

Transducer Mechanism: G Protein–Coupled Receptors01:30

Transducer Mechanism: G Protein–Coupled Receptors

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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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GPCR Desensitization01:12

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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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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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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.
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: Aug 12, 2025

Monitoring GPCR-β-arrestin1/2 Interactions in Real Time Living Systems to Accelerate Drug Discovery
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Bias-force guided simulations combined with experimental validations towards GPR17 modulators identification.

Sana Kari1, Akshaya Murugesan1, Ramesh Thiyagarajan2

  • 1Molecular Signaling Group, Faculty of Medicine and Health Technology, Tampere University and BioMediTech, P.O.Box 553, 33101 Tampere, Finland.

Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie
|January 30, 2023
PubMed
Summary

Glioblastoma Multiforme (GBM) is a deadly brain cancer. Researchers identified Sacubitril and Vorapaxar as potential drugs targeting GPR17, a protein crucial for GBM progression, offering new hope for treatment.

Keywords:
Bias-force simulationForskolin-stimulated cAMP accumulationGPR17Orphan-GPCRsRemyelination

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Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • Glioblastoma Multiforme (GBM) is the most aggressive adult brain tumor with poor prognosis.
  • GBM cells exhibit resistance to conventional therapies due to self-renewal capacity.
  • GPR17, an orphan G protein-coupled receptor, is highly expressed in GBM and drives disease progression.

Purpose of the Study:

  • To identify high-affinity GPR17 modulators for potential GBM treatment.
  • To explore drug repurposing for targeting GPR17 in GBM.
  • To validate computational predictions through experimental methods.

Main Methods:

  • Virtual screening of 1379 FDA-approved drugs against the GPR17 orthosteric binding pocket.
  • Biased-force pulling molecular dynamic (MD) simulations to predict drug-target interactions.
  • Experimental validation using GBM cell lines (LN229, SNB19) and cAMP accumulation assays.

Main Results:

  • Four FDA-approved drugs (Sacubitril, Victrelis, Pralatrexate, Vorapaxar) were identified as top GPR17 modulator candidates.
  • Sacubitril demonstrated full agonist activity, while Vorapaxar showed partial agonist activity for GPR17.
  • Sacubitril exhibited potent activity with pEC50 values of 4.841 (LN229) and 4.661 (SNB19).
  • siRNA-mediated GPR17 silencing confirmed Sacubitril's targeted binding.

Conclusions:

  • Sacubitril and Vorapaxar are identified as promising GPR17-specific drugs for GBM repurposing.
  • This study highlights novel therapeutic opportunities for aggressive brain tumors.
  • The findings pave the way for developing new treatments for GPR17-related diseases.