Binding or Bending: Distinction of Allosteric Abl Kinase Agonists from Antagonists by an NMR-Based Conformational Assay
| Autor: | Simona Cotesta, André Strauss, Jürgen Mestan, Xavier Pelle, Sandra W. Cowan-Jacob, Andreas Marzinzik, Wolfgang Jahnke, Pascal Furet, Robert Martin Grotzfeld, Doriano Fabbro, Gabriele Fendrich |
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| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Conformational change Magnetic Resonance Spectroscopy Stereochemistry Allosteric regulation Drug Evaluation Preclinical Plasma protein binding Ligands Myristic Acid Biochemistry Protein Structure Secondary Catalysis Mice Colloid and Surface Chemistry Protein structure Allosteric Regulation hemic and lymphatic diseases Animals Humans Proto-Oncogene Proteins c-abl Protein Kinase Inhibitors ABL Chemistry Assay General Chemistry Nuclear magnetic resonance spectroscopy Enzyme Activation Helix Protein Binding |
| Zdroj: | Journal of the American Chemical Society. 132:7043-7048 |
| ISSN: | 1520-5126 0002-7863 |
| DOI: | 10.1021/ja101837n |
| Popis: | Allosteric inhibitors of Bcr-Abl have emerged as a novel therapeutic option for the treatment of CML. Using fragment-based screening, a search for novel Abl inhibitors that bind to the myristate pocket was carried out. Here we show that not all myristate ligands are functional inhibitors, but that the conformational state of C-terminal helix_I is a structural determinant for functional activity. We present an NMR-based conformational assay to monitor the conformation of this crucial helix_I and show that myristate ligands that bend helix_I are functional antagonists, whereas ligands that bind to the myristate pocket but do not induce this conformational change are kinase agonists. Activation of c-Abl by allosteric agonists has been confirmed in a biochemical assay. |
| Databáze: | OpenAIRE |
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