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Related Concept Videos

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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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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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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 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 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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Tuning RXR Modulators for PGC1α Recruitment.

Felix Nawa1, Minh Sai1, Jan Vietor1

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Summary
This summary is machine-generated.

Synthetic agonists selectively recruit PGC1α to nuclear retinoid X receptors (RXRs), unlike endogenous ligands. This selective coregulator modulation offers potential for targeted RXR-based therapies.

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Area of Science:

  • Molecular biology
  • Endocrinology
  • Pharmacology

Background:

  • Nuclear retinoid X receptors (RXRs) regulate gene expression via ligand-dependent corepressor release and coactivator recruitment.
  • The diverse coactivator binding of RXRs suggests potential for selective activation through ligand modulation.
  • Targeting RXR-coregulator interactions could enable tissue- or gene-selective therapeutic strategies.

Purpose of the Study:

  • To investigate the selective recruitment of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) to RXR by synthetic agonists.
  • To develop novel RXR agonists capable of differential PGC1α interaction for therapeutic applications.

Main Methods:

  • Identification of a synthetic agonist that strongly induces PGC1α binding to RXR.
  • Structure-guided design and synthesis of related RXR agonists.
  • Assessment of PGC1α recruitment in cell-free and cellular assays.

Main Results:

  • A synthetic agonist, distinct from 9-cis retinoic acid, significantly enhanced PGC1α binding to RXR.
  • Structurally related agonists exhibited varying capacities for promoting PGC1α recruitment.
  • Selective modulation of RXR-PGC1α interaction was demonstrated in both in vitro and cellular settings.

Conclusions:

  • Ligand-induced selective coregulator recruitment to RXR is achievable using molecular glues.
  • Targeting the RXR-PGC1α interaction presents a promising avenue for developing novel therapeutics.
  • This approach may lead to new treatment strategies by exploiting RXR pathway selectivity.