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Structure paper

TitleStructural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT receptors.
Journal, issue, pagesNat Struct Mol Biol, Year 2024
Publish dateMay 2, 2024
AuthorsUriel López-Sánchez / Lachlan Jake Munro / Lucy Kate Ladefoged / Anders Juel Pedersen / Christian Colding Brun / Signe Meisner Lyngby / Delphine Baud / Céline Juillan-Binard / Miriam Grønborg Pedersen / Sarah C R Lummis / Benny Bang-Andersen / Birgit Schiøtt / Christophe Chipot / Guy Schoehn / Jacques Neyton / Francois Dehez / Hugues Nury / Anders S Kristensen /
PubMed AbstractVortioxetine (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.
External linksNat Struct Mol Biol / PubMed:38698207
MethodsEM (single particle)
Resolution2.98 - 3.3 Å
Structure data

15689

8aw2

EMDB-15689, PDB-8aw2:
Mouse serotonin 5-HT3A receptor in complex with vortioxetine
Method: EM (single particle) / Resolution: 3.01 Å

15699

8axd

EMDB-15699, PDB-8axd:
Human serotonin 5-HT3A receptor (apo, resting conformation)
Method: EM (single particle) / Resolution: 2.98 Å

16103

8bl8

EMDB-16103, PDB-8bl8:
Human serotonin 5-HT3A receptor (apo, active/distorted conformation)
Method: EM (single particle) / Resolution: 3.21 Å

16104

8bla

EMDB-16104, PDB-8bla:
Human serotonin 5-HT3A receptor in complex with vortioxetine (detergent, ECD only, active/distorted conformation)
Method: EM (single particle) / Resolution: 3.3 Å

16105

8blb

EMDB-16105, PDB-8blb:
Human serotonin 5-HT3A receptor in complex with vortioxetine (nanodiscs, ECD, active/distorted conformation)
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-CL:
Unknown entry / Chloride


ChemComp, No image

ChemComp-VTX:
Unknown entry

Source
  • mus musculus (house mouse)
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Pentameric ligand-gated ion channel / Serotonin receptor / vortioxetine / Human pentameric ligand-gated ion channel / Human serotonin receptor

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