Structural basis for the transmembrane signaling and antidepressant-induced activation of the receptor tyrosine kinase TrkB

Erik F. Kot, Sergey A. Goncharuk, María Luisa Franco, Daniel M. McKenzie, Alexander S. Arseniev, Andrea Benito-Martínez, Mario Costa, Antonino Cattaneo, Kalina Hristova, Marçal Vilar () and Konstantin S. Mineev ()
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Erik F. Kot: Shenzhen MSU-BIT University
Sergey A. Goncharuk: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry
María Luisa Franco: Instituto de Biomedicina de Valencia-CSIC
Daniel M. McKenzie: Johns Hopkins University
Alexander S. Arseniev: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry
Andrea Benito-Martínez: Instituto de Biomedicina de Valencia-CSIC
Mario Costa: Scuola Normale Superiore Laboratory of Biology BIO@SNS
Antonino Cattaneo: Scuola Normale Superiore Laboratory of Biology BIO@SNS
Kalina Hristova: Johns Hopkins University
Marçal Vilar: Instituto de Biomedicina de Valencia-CSIC
Konstantin S. Mineev: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-53710-7

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