Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT3 receptors
Résumé
Vortioxetine (VTX) is a recent antidepressant that targets a variety of serotonin receptors. We investigate
the drug’s molecular mechanism of operation at serotonin 5-HT3 receptors (5-HT3R), which features two
mysterious properties: VTX acts differently on rodent and human 5-HT3R; VTX appears to suppress any
subsequent response to agonists. Using a combination of cryo-EM, electrophysiology, and molecular
dynamics, we show that VTX stabilizes a resting inhibited state of the mouse 5-HT3R and an agonist boundlike state of the 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
Domaines
Sciences du Vivant [q-bio]| Origine | Fichiers produits par l'(les) auteur(s) |
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