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Videos de Conceptos Relacionados

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

Transducer Mechanism: G Protein–Coupled Receptors

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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.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
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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
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
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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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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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Video Experimental Relacionado

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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Codificación y decodificación de la selectividad y la promiscuidad en la red de interacción quimioquina-GPCR humana

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
Resumen

Los investigadores identificaron los determinantes moleculares clave que rigen las interacciones de las quimiocinas y los receptores acoplados a proteínas G (GPCR). La comprensión de estos elementos permite la ingeniería de nuevas quimioquinas para aplicaciones terapéuticas.

Palabras clave:
GPCR y sus derivadosLas quimiocinasquimiotaxisCiencia de los datosAprendizaje automáticoPolimorfismoInteracción proteína-proteínaDeterminantes de la selectividadmotivo lineal cortoProteínas no estructuradas

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Área de la Ciencia:

  • Inmunología
  • Biología molecular
  • Biología estructural

Sus antecedentes:

  • Las interacciones con los receptores de quimiocinas son cruciales para la migración celular, formando una red compleja que involucra a 46 ligandos y 23 receptores acoplados a proteínas G (GPCR).
  • La base molecular para la unión selectiva y promiscua de las quimiocinas a sus GPCR sigue siendo en gran medida desconocida a pesar de los andamios estructurales compartidos.

Objetivo del estudio:

  • Aclarar los principios moleculares que dictan la selectividad y la promiscuidad en las interacciones quimioquina-GPCR.
  • Identificar los determinantes conservados y variables responsables de mediar estas interacciones específicas proteína-proteína.

Principales métodos:

  • Análisis de determinantes conservados, semiconservados y variables dentro de las secuencias de quimiocinas y GPCR.
  • Reconocimiento combinatorio de estos determinantes por ligandos y receptores a través de regiones de proteínas estructuradas y no estructuradas.
  • Ingeniería de una quimioquina viral para demostrar preferencias de acoplamiento de GPCR alteradas basadas en principios identificados.

Principales resultados:

  • Identificación de un conjunto de elementos de reconocimiento conservados y variables que rigen la especificidad de unión de las quimiocinas y los GPCR.
  • Demostración de que la selectividad y la promiscuidad surgen de una combinación de determinantes generalizados y específicos.
  • Ingeniería exitosa de una quimioquina viral con perfiles de interacción GPCR modificados.

Conclusiones:

  • La especificidad de la interacción quimioquina-GPCR se determina mediante un código combinatorio de determinantes moleculares conservados y variables.
  • Estos hallazgos proporcionan un marco para la comprensión y la ingeniería de las interacciones quimioquina-GPCR.
  • El estudio ofrece un recurso web para ayudar en el diseño de proteínas para el desarrollo de inmunoterápicos y terapias celulares.