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Related Concept Videos

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.
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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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IP3/DAG Signaling Pathway01:11

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Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the  phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...
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GPCRs Regulate Adenylyl Cylase Activity01:09

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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.
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Assembly of Signaling Complexes01:30

Assembly of Signaling Complexes

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Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
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Related Experiment Video

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Pro-phagocytic function and structural basis of GPR84 signaling.

Xuan Zhang1,2, Yujing Wang1, Shreyas Supekar3

  • 1Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.

Nature Communications
|September 14, 2023
PubMed
Summary

GPR84 activation enhances macrophage phagocytosis of cancer cells, particularly when combined with CD47 blockade. This study reveals the GPR84 structure, offering insights into its signaling and potential drug development for cancer therapy.

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Area of Science:

  • Immunology
  • Structural Biology
  • Pharmacology

Background:

  • GPR84 is a G protein-coupled receptor (GPCR) activated by medium-chain fatty acids (MCFAs).
  • GPR84 signaling is primarily pro-inflammatory and promotes macrophage phagocytosis.
  • Targeting GPR84 presents a potential strategy for cancer immunotherapy.

Purpose of the Study:

  • To investigate the synergistic effect of GPR84 activation and CD47 blockade on cancer cell phagocytosis.
  • To determine the high-resolution structure of the GPR84-Gi signaling complex.
  • To elucidate the molecular mechanisms underlying GPR84 activation, ligand binding, and selectivity.

Main Methods:

  • Utilized a synthetic GPR84 agonist (6-OAU) and CD47 blockade in cancer cell-macrophage co-cultures.
  • Determined the crystal structure of the GPR84-Gi signaling complex.
  • Performed computational docking and molecular simulations.

Main Results:

  • GPR84 activation synergizes with CD47 blockade to enhance macrophage-mediated cancer cell phagocytosis.
  • The determined structure reveals an occluded 6-OAU binding pocket and an unusual Gi-coupling interface.
  • Structural and computational data suggest mechanisms for MCFA selectivity and ligand interaction with GPR84.

Conclusions:

  • GPR84 plays a significant role in modulating macrophage phagocytic activity against cancer cells.
  • The high-resolution structure provides critical insights into GPR84 activation and signaling pathways.
  • This research lays the groundwork for developing novel GPR84-targeted therapeutics for cancer treatment.