Structural Determinants for Activity of the Antidepressant Vortioxetine at Human and Rodent 5-HT3 receptors

Lopez-Sanchez, U.; Munro, L. J.; Ladefoged, L. K.; Pedersen, A. J.; Brun, C. C.; Lyngby, S. M.; Baud, D.; Pedersen, M. G.; Lummis, S. C. R.; Bang-Andersen, B.; Schiott, B.; Chipot, C.; Schoehn, G.; Neyton, J.; Dehez, F.; Nury, H.; Kristensen, A. S.

doi:10.1101/2024.02.23.581731

bioRxiv · 10.1101/2024.02.23.581731

Structural Determinants for Activity of the Antidepressant Vortioxetine at Human and Rodent 5-HT3 receptors

Lopez-Sanchez, U.·Munro, L. J.·Ladefoged, L. K.·Pedersen, A. J.·Brun, C. C.·Lyngby, S. M.·Baud, D.·Pedersen, M. G.·Lummis, S. C. R.·Bang-Andersen, B.·Schiott, B.·Chipot, C.·Schoehn, G.·Neyton, J.·Dehez, F.·Nury, H.·Kristensen, A. S.

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Abstract

Vortioxetine (VTX) is a recent antidepressant that targets a variety of serotonin receptors. We investigate the drugs 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 bound-like 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.

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Lopez-Sanchez, U., Munro, L. J., Ladefoged, L. K., Pedersen, A. J., Brun, C. C., Lyngby, S. M., Baud, D., Pedersen, M. G., Lummis, S. C. R., Bang-Andersen, B., Schiott, B., Chipot, C., Schoehn, G., Neyton, J., Dehez, F., Nury, H., Kristensen, A. S.. 2024-02-24. Structural Determinants for Activity of the Antidepressant Vortioxetine at Human and Rodent 5-HT3 receptors. https://doi.org/10.1101/2024.02.23.581731

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