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Phosphorylation01:02

Phosphorylation

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The addition or removal of phosphate groups from proteins is the most common chemical modification that regulates cellular processes. These modifications can affect the structure, activity, stability, and localization of proteins within cells as well as their interactions with other proteins.
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...
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Phosphoinositides and PIPs01:42

Phosphoinositides and PIPs

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Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
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Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

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When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
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Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

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Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
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Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

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Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

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Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
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Updated: Dec 12, 2025

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

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Pequeñas moléculas quiméricas que inducen la fosforilación

Sachini U Siriwardena1,2, Dhanushka N P Munkanatta Godage1,2, Veronika M Shoba1,2

  • 1Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.

Journal of the American Chemical Society
|August 14, 2020
PubMed
Resumen
Este resumen es generado por máquina.

Las nuevas moléculas pequeñas bifuncionales, llamadas moléculas quiméricas pequeñas inductoras de fosforilación (PHICS), pueden reclutar quinasas para fosforilar proteínas objetivo. Este enfoque permite un nuevo control de la fosforilación de proteínas para la investigación y las aplicaciones terapéuticas.

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Área de la Ciencia:

  • Biología Química
  • Biología molecular
  • Descubrimiento de drogas

Sus antecedentes:

  • Las moléculas pequeñas inhiben tradicionalmente la actividad de las enzimas.
  • Las estrategias emergentes utilizan moléculas pequeñas para inducir nuevas funciones enzimáticas a través de efectos de proximidad.
  • La fosforilación de proteínas es un mecanismo regulador clave que altera la estructura y la función de las proteínas.

Objetivo del estudio:

  • Desarrollar nuevas moléculas pequeñas que induzcan la fosforilación de las proteínas objetivo.
  • Investigar el potencial de la proximidad diseñada para controlar la actividad de la quinasa.
  • Para explorar la utilidad de estas moléculas en la investigación básica y la medicina.

Principales métodos:

  • Diseño y síntesis de moléculas quiméricas pequeñas inductoras de la fosforilación (PHICS).
  • PHICS enlaza enlaces de moléculas pequeñas para una quinasa específica y una proteína diana.
  • Ensayos de desarrollo para medir la actividad de la quinasa y la fosforilación de las proteínas.

Principales resultados:

  • PHICS reclutó con éxito AMPK y PKC para fosforilar las proteínas no substratas.
  • Se ha demostrado una fosforilación dependiente de la dosis, el control temporal y la proximidad.
  • Las fosforilaciones nativas y neo-fosforilaciones de BRD4 y la fosforilación relevante para la señalización de la tirosina quinasa de Bruton en las células.

Conclusiones:

  • Los PHICS representan una nueva clase de moléculas bifuncionales para la fosforilación dirigida de proteínas.
  • Esta tecnología permite un control preciso de los eventos nativos y de neofosforilación.
  • La fosforilación mediada por PHICS tiene un potencial significativo para el avance de la investigación biológica y las estrategias terapéuticas.