ArticleBiochimica et biophysica acta2010
A monovalent agonist of TrkA tyrosine kinase receptors can be converted into a bivalent antagonist.
Article in Biochimica et biophysica acta, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 19 citations in OpenAlex.
- Selective Modulation of Trk Receptors byACS chemical neuroscience · 2025Article
- Selective inhibitors of the TrkC.T1 receptor reduce retinal inflammation and delay neuronal death in a model of retinitis pigmentosa.PNAS nexus · 2025Article
- Selective, Intrinsically Fluorescent Trk Modulating Probes.ACS chemical neuroscience · 2024Article
- hNGF Peptides Elicit the NGF-TrkA Signalling Pathway in Cholinergic Neurons and Retain Full Neurotrophic Activity in the DRG Assay.Biomolecules · 2020Article
- A C-terminal cysteine residue is required for peptide-based inhibition of the NGF/TrkA interaction at nM concentrations: implications for peptide-based analgesics.Scientific reports · 2019Article
- Neuroprotection: Pro-survival and Anti-neurotoxic Mechanisms as Therapeutic Strategies in Neurodegeneration.Frontiers in cellular neuroscience · 2019Review
- The Paradoxical Signals of Two TrkC Receptor Isoforms Supports a Rationale for Novel Therapeutic Strategies in ALS.PloS one · 2016Article
- A Pro-Nerve Growth Factor (proNGF) and NGF Binding Protein, α2-Macroglobulin, Differentially Regulates p75 and TrkA Receptors and Is Relevant to Neurodegeneration Ex Vivo and In Vivo.Molecular and cellular biology · 2015Article
- Combinatorial assembly of small molecules into bivalent antagonists of TrkC or TrkA receptors.PloS one · 2014Article
- Comparison of nerve growth factor receptor binding models using heterodimeric muteins.Journal of neuroscience research · 2012Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
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 SIGNIFICANCE: we report a small molecule monovalent agonist being converted to a bivalent antagonist.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.