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Related Concept Videos

Phosphorylation01:02

Phosphorylation

53.3K
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...
16.5K
Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

14.5K
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...
14.5K
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:
3.6K

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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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Phosphorylation-Inducing Chimeric Small Molecules.

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
Summary
This summary is machine-generated.

New bifunctional small molecules, called phosphorylation-inducing chimeric small molecules (PHICS), can recruit kinases to phosphorylate target proteins. This approach enables novel control over protein phosphorylation for research and therapeutic applications.

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Area of Science:

  • Chemical Biology
  • Molecular Biology
  • Drug Discovery

Background:

  • Small molecules traditionally inhibit enzyme activity.
  • Emerging strategies utilize small molecules to induce new enzyme functions through proximity effects.
  • Protein phosphorylation is a key regulatory mechanism altering protein structure and function.

Purpose of the Study:

  • To develop novel small molecules that induce phosphorylation of target proteins.
  • To investigate the potential of engineered proximity for controlling kinase activity.
  • To explore the utility of these molecules in basic research and medicine.

Main Methods:

  • Design and synthesis of phosphorylation-inducing chimeric small molecules (PHICS).
  • PHICS link small-molecule binders for a specific kinase and target protein.
  • Assay development to measure kinase activity and protein phosphorylation.

Main Results:

  • PHICS successfully recruited AMPK and PKC to phosphorylate non-substrate proteins.
  • Demonstrated dose-dependent, temporal control, and proximity-dependent phosphorylation.
  • Induced native and neo-phosphorylations of BRD4 and signaling-relevant phosphorylation of Bruton's tyrosine kinase in cells.

Conclusions:

  • PHICS represent a new class of bifunctional molecules for targeted protein phosphorylation.
  • This technology allows for precise control over native and neo-phosphorylation events.
  • PHICS-mediated phosphorylation holds significant potential for advancing biological research and therapeutic strategies.