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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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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

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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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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 Coupled Receptors01:21

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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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Current Trends in GPCR Allostery.

Khuraijam Dhanachandra Singh1, Sadashiva S Karnik2

  • 1Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.

The Journal of Membrane Biology
|January 20, 2021
PubMed
Summary

Allosteric drugs offer a safer approach to targeting G protein-coupled receptors (GPCRs), a major drug target. They modulate receptor signals selectively, avoiding side effects associated with blocking all receptor activity.

Keywords:
Allosteric ligandAutoantibodiesCADDGpcrs

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Area of Science:

  • Pharmacology
  • Drug Discovery
  • Structural Biology

Background:

  • G protein-coupled receptors (GPCRs) are crucial drug targets, accounting for approximately 34% of FDA-approved medications.
  • Current drug development focuses on precise modulation of GPCR signaling for specific disorders.
  • Classical orthosteric drugs inhibit all GPCR signals by blocking endogenous ligand binding, potentially causing adverse effects.

Purpose of the Study:

  • To explore the advantages of allosteric drugs in GPCR-targeted therapies.
  • To review GPCR crystal structures determined with allosteric ligands.
  • To discuss current clinical applications and trials of allosteric drugs.

Main Methods:

  • Review of scientific literature on GPCRs and allosteric modulation.
  • Analysis of GPCR crystal structures complexed with allosteric ligands.
  • Compilation of data on allosteric drugs in clinical use or trials.

Main Results:

  • Allosteric drugs modulate GPCR signaling without preventing endogenous ligand binding.
  • This selective modulation allows for the preservation of beneficial signaling pathways.
  • GPCR crystal structures reveal specific binding sites for allosteric modulators.

Conclusions:

  • Allosteric drugs represent a significant advancement in GPCR-targeted pharmacology.
  • They offer a promising strategy to enhance therapeutic efficacy while minimizing side effects.
  • Further research and clinical trials are essential to fully realize the potential of allosteric drugs.