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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
Defying c-Abl signaling circuits through small allosteric compounds
1Department of Biology, University of Rome Tor Vergata , Rome, Italy.
Abstract:
Many extracellular and intracellular signals promote the c-Abl tyrosine kinase activity. c-Abl in turn triggers a multitude of changes either in protein phosphorylation or in gene expression in the cell. Yet, c-Abl takes part in diverse signaling routes because of several domains linked to its catalytic core. Complex conformational changes turn on and off its kinase activity. These changes affect surface features of the c-Abl kinase and likely its capability to bind actin and/or DNA. Two specific inhibitors (ATP-competitive or allosteric compounds) regulate the c-Abl kinase through different mechanisms. NMR studies show that a c-Abl fragment (SH3-SH2-linker-SH1) adopts different conformational states upon binding to each inhibitor. This supports an unconventional use for allosteric compounds to unraveling physiological c-Abl signaling circuits.
Insights
The c-Abl tyrosine kinase
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Signaling
Background:
- Extracellular and intracellular signals activate c-Abl tyrosine kinase.
- c-Abl influences protein phosphorylation and gene expression via its domains.
- Kinase activity is regulated by conformational changes affecting binding to actin and DNA.
Purpose of the Study:
- To investigate the regulatory mechanisms of c-Abl kinase activity.
- To explore the distinct effects of ATP-competitive and allosteric inhibitors on c-Abl conformation.
- To understand how allosteric compounds can elucidate physiological c-Abl signaling.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy was employed.
- A specific c-Abl fragment (SH3-SH2-linker-SH1) was studied.
- The conformational changes upon inhibitor binding were analyzed.
Main Results:
- NMR studies revealed distinct conformational states of the c-Abl fragment with each inhibitor.
- ATP-competitive and allosteric inhibitors induce different structural changes.
- These findings highlight the differential regulation of c-Abl.
Conclusions:
- Allosteric compounds offer a unique approach to studying c-Abl signaling pathways.
- Understanding c-Abl conformational dynamics is crucial for deciphering its biological roles.
- This research provides insights into targeted therapeutic strategies for c-Abl-related conditions.
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