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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature Structural and Molecular Biology |
| ISSN | 1545-9993 |
| DOI | |
| Status | Accepteret/In press - 2024 |
Bibliografisk note
Funding Information:
This work was supported by the Danish Council of Independent Research for Medical Sciences (grant number DFF-404-00309, A.S.K.), the Lundbeck Foundation (grant number 2017-1655 and 2012-12453, A.S.K.), the Carlsberg Foundation (A.S.K.), the ERC Starting grant 637733 Pentabrain (HN), the Fondation pour la Recherche M\u00E9dicale (grant number SPF201809007073, U.L.S.), the State-Region Plan \u201CTechnological Innovations, Modeling and Personalized Medical Support\u201D (IT2MP, to F.D.) and the European Regional Development Funds (ERDF, to F.D.). Computations were made possible through allocations at the Centre for Scientific Computing, Aarhus (SCS-Aa). We acknowledge access to the ESRF CM01 Krios microscope. The work used the platforms of the Grenoble Instruct-ERIC center (ISBG; UMS 3518 CNRS-CEA-UGA-EMBL) within the Grenoble Partnership for Structural Biology (PSB), supported by FRISBI (ANR-10-INBS-05-02) and GRAL, financed within the University Grenoble Alpes graduate school (Ecoles Universitaires de Recherche) CBH-EUR-GS (ANR-17-EURE-0003). The electron microscopy facility is supported by the Rh\u00F4ne-Alpes Region, the FRM, the FEDER, and the GIS-IBISA. We thank L. Zarkadas for his help with cryoEM.
Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
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