8OYD

TrkB transmembrane domain NMR structure in DMPC/DHPC bicelles

Summary for 8OYD

• Entry DOI: 10.2210/pdb8oyd/pdb
• NMR Information: BMRB: 34814
• Descriptor: BDNF/NT-3 growth factors receptor (1 entity in total)
• Functional Keywords: protein, receptor, neurotrophin, bdnf, nt-4, tmd, dimer, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 9950.20

Authors

Kot, E.F.,Mineev, K.S.,Goncharuk, S.A. (deposition date: 2023-05-04, release date: 2024-05-15, Last modification date: 2024-11-13)

Primary citation

Kot, E.F.,Goncharuk, S.A.,Franco, M.L.,McKenzie, D.M.,Arseniev, A.S.,Benito-Martinez, A.,Costa, M.,Cattaneo, A.,Hristova, K.,Vilar, M.,Mineev, K.S.
Structural basis for the transmembrane signaling and antidepressant-induced activation of the receptor tyrosine kinase TrkB.
Nat Commun, 15:9316-9316, 2024

PubMed 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.

PubMed: 39472452
DOI: 10.1038/s41467-024-53710-7

Experimental method

SOLUTION NMR