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Title | Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT receptors. |
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Journal, issue, pages | Nat Struct Mol Biol, Vol. 31, Issue 8, Page 1232-1242, Year 2024 |
Publish date | May 2, 2024 |
![]() | Uriel López-Sánchez / Lachlan Jake Munro / Lucy Kate Ladefoged / Anders Juel Pedersen / Christian Colding Brun / Signe Meisner Lyngby / Delphine Baud / Céline Juillan-Binard / Miriam Grønlund Pedersen / Sarah C R Lummis / Benny Bang-Andersen / Birgit Schiøtt / Christophe Chipot / Guy Schoehn / Jacques Neyton / Francois Dehez / Hugues Nury / Anders S Kristensen / ![]() ![]() ![]() ![]() |
PubMed Abstract | 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-HT receptor ...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-HT receptor (5-HTR), which features two properties: VTX acts differently on rodent and human 5-HTR, 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-HTR and an agonist-bound-like state of human 5-HTR, in line with the functional profile of the drug. We report four human 5-HTR 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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Methods | EM (single particle) |
Resolution | 2.98 - 3.3 Å |
Structure data | EMDB-15689, PDB-8aw2: EMDB-15699, PDB-8axd: EMDB-16103, PDB-8bl8: EMDB-16104, PDB-8bla: EMDB-16105, PDB-8blb: |
Chemicals | ![]() ChemComp-NAG: ![]() ChemComp-CL: ![]()
ChemComp-VTX: |
Source |
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![]() | MEMBRANE PROTEIN / Pentameric ligand-gated ion channel / Serotonin receptor / vortioxetine / Human pentameric ligand-gated ion channel / Human serotonin receptor |