Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT3 receptors
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Vortioxetine (VTX) is a recently approved antidepressant that targets a variety of serotonin receptors. Here, we investigate the drug’s molecular mechanism of operation at the serotonin 5-HT3 receptor (5-HT3R), which features two properties: VTX acts differently on rodent and human 5-HT3R, and VTX appears to suppress any subsequent response to agonists. Using a combination of cryo-EM, electrophysiology, voltage-clamp fluorometry and molecular dynamics, we show that VTX stabilizes a resting inhibited state of the mouse 5-HT3R and an agonist-bound-like state of human 5-HT3R, in line with the functional profile of the drug. We report four human 5-HT3R structures and show that the human receptor transmembrane domain is intrinsically fragile. We also explain the lack of recovery after VTX administration via a membrane partition mechanism.
Original language | English |
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Journal | Nature Structural and Molecular Biology |
Volume | 31 |
Pages (from-to) | 1232–1242 |
ISSN | 1545-9993 |
DOIs | |
Publication status | Published - 2024 |
Bibliographical note
Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
ID: 391501390