Structural basis for the transmembrane signaling and antidepressant-induced activation of the receptor tyrosine kinase TrkB.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
29 Oct 2024
29 Oct 2024
Historique:
received:
07
06
2023
accepted:
18
10
2024
medline:
30
10
2024
pubmed:
30
10
2024
entrez:
30
10
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39472452
doi: 10.1038/s41467-024-53710-7
pii: 10.1038/s41467-024-53710-7
doi:
Substances chimiques
Fluoxetine
01K63SUP8D
Receptor, trkB
EC 2.7.10.1
Antidepressive Agents
0
tropomyosin-related kinase-B, human
EC 2.7.10.1
Membrane Glycoproteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
9316Subventions
Organisme : Russian Science Foundation (RSF)
ID : 22-14-00130
Organisme : Regional Government of Valencia | Conselleria d'Educació, Investigació, Cultura i Esport (Conselleria d'Educació, Investigació, Cultura i Esport de la Generalitat Valenciana)
ID : INVEST/2022/456
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : CRC 1507
Informations de copyright
© 2024. The Author(s).
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