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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 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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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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Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
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Molecular glues as potential GPCR therapeutics.

Bryan L Roth1, Brian E Krumm2

  • 1Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Biochemical Pharmacology
|June 30, 2024
PubMed
Summary

Molecular glues are small molecules that enhance protein interactions. Some GPCR allosteric modulators function as molecular glues, influencing transducer signaling for drug development.

Keywords:
AllosterismBiased signalingG proteinsGPCR

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Area of Science:

  • Pharmacology
  • Biochemistry
  • Structural Biology

Background:

  • Molecular glues are small molecules that promote protein-protein interactions.
  • G protein-coupled receptor (GPCR) allosteric modulators typically act at a distance from the receptor-transducer interface.
  • Recent structural data reveals GPCR allosteric modulators can interact directly at the interface.

Purpose of the Study:

  • To explore the dual role of GPCR allosteric modulators as molecular glues.
  • To discuss the implications of these findings for molecular tools and drug development.

Main Methods:

  • Analysis of recent structural data of GPCR G protein complexes.
  • Comparative analysis of allosteric modulator mechanisms.

Main Results:

  • Some GPCR allosteric modulators function as molecular glues, binding to both the receptor and transducer.
  • These molecular glue allosteric modulators can bias transducer signaling positively or negatively.
  • The effect is dependent on the specific transducer involved.

Conclusions:

  • GPCR allosteric modulators can act as molecular glues, directly mediating protein-protein interactions.
  • This mechanism offers new possibilities for developing targeted molecular tools.
  • Understanding this role is crucial for future drug discovery and development strategies.