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Related Concept Videos

GPCR Desensitization01:12

GPCR Desensitization

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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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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

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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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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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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Selectins01:25

Selectins

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Cell adhesion is  an essential aspect of multicellularity. While stable cell interactions usually occur between cells of the same type, transient cell interactions occur between cells of different tissue types, such as between neutrophils and endothelial cells. Selectins are one class of cell adhesion molecules (CAMs) that bind carbohydrate ligands to form transient cell adhesion. They are rod-like proteins with a long extracellular part of variable length ending with the lectin domain,...
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Updated: May 10, 2025

A Flow Cytometry-based Assay to Identify Compounds That Disrupt Binding of Fluorescently-labeled CXC Chemokine Ligand 12 to CXC Chemokine Receptor 4
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Encoding and decoding selectivity and promiscuity in the human chemokine-GPCR interaction network.

Andrew B Kleist1, Martyna Szpakowska2, Lindsay J Talbot3

  • 1Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA; Medical Scientist Training Program, Medical College of Wisconsin, Milwaukee, WI, USA; MRC Laboratory of Molecular Biology, Cambridge, UK.

Cell
|April 24, 2025
PubMed
Summary

Researchers identified key molecular determinants governing chemokine and G-protein-coupled receptor (GPCR) interactions. Understanding these elements enables engineering novel chemokines for therapeutic applications.

Keywords:
GPCRchemokinechemotaxisdata sciencemachine learningpolymorphismprotein-protein interactionselectivity determinantsshort linear motifunstructured protein

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Optimizing the Genetic Incorporation of Chemical Probes into GPCRs for Photo-crosslinking Mapping and Bioorthogonal Chemistry in Live Mammalian Cells
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Area of Science:

  • Immunology
  • Molecular Biology
  • Structural Biology

Background:

  • Chemokine-receptor interactions are crucial for cell migration, forming a complex network involving 46 ligands and 23 G-protein-coupled receptors (GPCRs).
  • The molecular basis for the selective and promiscuous binding of chemokines to their GPCRs remains largely unknown despite shared structural scaffolds.

Purpose of the Study:

  • To elucidate the molecular principles that dictate selectivity and promiscuity in chemokine-GPCR interactions.
  • To identify conserved and variable determinants responsible for mediating these specific protein-protein interactions.

Main Methods:

  • Analysis of conserved, semi-conserved, and variable determinants within chemokine and GPCR sequences.
  • Combinatorial recognition of these determinants by ligands and receptors across structured and unstructured protein regions.
  • Engineering a viral chemokine to demonstrate altered GPCR coupling preferences based on identified principles.

Main Results:

  • Identification of a set of conserved and variable recognition elements that govern chemokine-GPCR binding specificity.
  • Demonstration that selectivity and promiscuity arise from a combination of generalized and specific determinants.
  • Successful engineering of a viral chemokine with modified GPCR interaction profiles.

Conclusions:

  • Chemokine-GPCR interaction specificity is determined by a combinatorial code of conserved and variable molecular determinants.
  • These findings provide a framework for understanding and engineering chemokine-GPCR interactions.
  • The study offers a web resource to aid in protein design for developing immunotherapeutics and cell therapies.