A monovalent agonist of TrkA tyrosine kinase receptors can be converted into a bivalent antagonist |
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Authors: | Fouad Brahimi Jing Liu Andrey Malakhov Shafinaz Chowdhury Enrico O Purisima Ljubica Ivanisevic Antoine Caron Kevin Burgess H Uri Saragovi |
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Institution: | 1. Lady Davis Institute-Jewish General Hospital, Pharmacology and Therapeutics, Oncology and the Cancer Center. McGill University, Canada H3T 1E2;2. Department of Chemistry, Texas A&M University, Box 30012, College Station, TX 77841, USA;3. Biotechnology Research Institute, National Research Council Canada, 6100 Royalmount Avenue, Montreal, Quebec, Canada H4P 2R2 |
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Abstract: | BackgroundReceptor tyrosine kinases (RTK) act through dimerization. Previously it was thought that only bivalent ligands could be agonistic, whereas monovalent ligands should be antagonistic. This notion changed after the demonstration that monovalent ligands can be agonistic, including our report of a small molecule monovalent ligand “D3” that is a partial agonist of the NGF receptor TrkA. A bivalent “D3-linker-D3” was expected to increase agonism.MethodsDimeric analogs were synthesized and tested in binding, biochemical, and biological assays.ResultsOne analog, 1-ss, binds TrkA with higher affinity than D3 and induces or stabilizes receptor dimers. However, 1-ss exhibited antagonistic activity, through two mechanisms. One mechanism is that 1-ss blocks NGF binding, unlike D3 which is non-competitive. Inhibition of NGF binding may be due to the linker of 1-ss filling the inter-receptor space that NGF traverses before docking. In a second mechanism, 1-ss acts as a pure antagonist, inhibiting NGF-independent TrkA activity in cells over-expressing receptors. Inhibition is likely due to 1-ss “freezing” the TrkA dimer in the inactive state.ConclusionsDimerization of an RTK can result in antagonism, through two independent mechanisms.General significancewe report a small molecule monovalent agonist being converted to a bivalent antagonist. |
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Keywords: | FACScan Fluoresence Activated Cell Scanner FITC Fluorescein isothiocyanate TEG Triethylene Glycol Trk Tropomyosin receptor kinase family NGF Nerve Growth Factor p75 Neurotrophin Receptor IGF-1 Insulin-like growth Factor-1 IGF-1R Insulin-like growth Factor-1 Receptor pTyr Phosphotyrosine RTK Receptor Tyrosine Kinase |
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