Divergent modulation of Src-family kinase regulatory interactions with ATP-competitive inhibitors
| Autor: | Dustin J. Maly, Ratika Krishnamurty, Gabriel J. Brighty, Ames C. Register, Stephen E. Leonard |
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| Rok vydání: | 2014 |
| Předmět: |
0303 health sciences
Kinase Effector 030302 biochemistry & molecular biology General Medicine Articles Biology SH2 domain Ligands Biochemistry 3. Good health Cell biology 03 medical and health sciences Adenosine Triphosphate src-Family Kinases Molecular Medicine Phosphorylation Src family kinase Signal transduction Cellular localization 030304 developmental biology Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | ACS Chemical Biology |
| ISSN: | 1554-8937 |
| Popis: | Multidomain protein kinases, central controllers of signal transduction, use regulatory domains to modulate catalytic activity in a complex cellular environment. Additionally, these domains regulate noncatalytic functions, including cellular localization and protein–protein interactions. Src-family kinases (SFKs) are promising therapeutic targets for a number of diseases and are an excellent model for studying the regulation of multidomain kinases. Here, we demonstrate that the regulatory domains of the SFKs Src and Hck are divergently affected by ligands that stabilize two distinct inactive ATP-binding site conformations. Conformation-selective, ATP-competitive inhibitors differentially modulate the ability of the SH3 and SH2 domains of Src and Hck to engage in intermolecular interactions and the ability of the kinase–inhibitor complex to undergo post-translational modification by effector enzymes. This surprising divergence in regulatory domain behavior by two classes of inhibitors that each stabilize inactive ATP-binding site conformations is found to occur through perturbation or stabilization of the αC helix. These studies provide insight into how conformation-selective, ATP-competitive inhibitors can be designed to modulate domain interactions and post-translational modifications distal to the ATP-binding site of kinases. |
| Databáze: | OpenAIRE |
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