A monovalent agonist of TrkA tyrosine kinase receptors can be converted into a bivalent antagonist

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DOIResolve DOI: http://doi.org/10.1016/j.bbagen.2010.06.007
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TypeArticle
Journal titleBiochimica et biophysica acta
Volume1800
Pages10181026; # of pages: 9
SubjectNeurotrophin; Ligand; Tyrosine kinase receptor; Linker; Agonist; Antagonist
AbstractReceptor 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. Methods: Dimeric analogs were synthesized and tested in binding, biochemical, and biological assays. Results: One 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. Conclusions: Dimerization of an RTK can result in antagonism, through two independent mechanisms. General significance: we report a small molecule monovalent agonist being converted to a bivalent antagonist.
Publication date
LanguageEnglish
AffiliationNational Research Council Canada (NRC-CNRC); NRC Biotechnology Research Institute
Peer reviewedYes
NRC number53133
NPARC number16512465
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Record identifier657a4604-f4a0-4418-87d2-fefdea105da9
Record created2010-12-14
Record modified2016-05-09
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