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Structural basis for the transmembrane signaling and antidepressant-induced activation of the receptor tyrosine kinase TrkB
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Structural basis for the transmembrane signaling and antidepressant-induced activation of the receptor tyrosine kinase TrkB
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Journal Article
Structural basis for the transmembrane signaling and antidepressant-induced activation of the receptor tyrosine kinase TrkB
2024
Overview
Neurotrophin receptors of the Trk family are involved in the regulation of brain development and neuroplasticity, and therefore can serve as targets for anti-cancer and stroke-recovery drugs, antidepressants, and many others. The structures of Trk protein domains in various states upon activation need to be elucidated to allow rational drug design. However, little is known about the conformations of the transmembrane and juxtamembrane domains of Trk receptors. In the present study, we employ NMR spectroscopy to solve the structure of the TrkB dimeric transmembrane domain in the lipid environment. We verify the structure using mutagenesis and confirm that the conformation corresponds to the active state of the receptor. Subsequent study of TrkB interaction with the antidepressant drug fluoxetine, and the antipsychotic drug chlorpromazine, provides a clear self-consistent model, describing the mechanism by which fluoxetine activates the receptor by binding to its transmembrane domain.
Neurotrophin receptor TrkB regulates neuronal growth and neuroplasticity. Here, the authors present the NMR structure of the intramembrane region of TrkB activated by antidepressant drugs, yielding insights into receptor function.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 14/63
/ 82/1
/ 82/16
/ 82/29
/ 82/6
/ 82/80
/ 82/83
/ Animals
/ Antidepressive Agents - chemistry
/ Antidepressive Agents - metabolism
/ Antidepressive Agents - pharmacology
/ Cell Membrane - drug effects
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Lipids
/ Magnetic resonance spectroscopy
/ NMR
/ Protein-tyrosine kinase receptors
/ Science
/ Signal Transduction - drug effects
/ Structure-function relationships
/ Tyrosine
