Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT3 receptors

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Standard

Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT3 receptors. / López-Sánchez, Uriel; Munro, Lachlan Jake; Ladefoged, Lucy Kate; Pedersen, Anders Juel; Brun, Christian Colding; Lyngby, Signe Meisner; Baud, Delphine; Juillan-Binard, Céline; Pedersen, Miriam Grønborg; Lummis, Sarah C.R.; Bang-Andersen, Benny; Schiøtt, Birgit; Chipot, Christophe; Schoehn, Guy; Neyton, Jacques; Dehez, Francois; Nury, Hugues; Kristensen, Anders S.

I: Nature Structural and Molecular Biology, 2024.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

López-Sánchez, U, Munro, LJ, Ladefoged, LK, Pedersen, AJ, Brun, CC, Lyngby, SM, Baud, D, Juillan-Binard, C, Pedersen, MG, Lummis, SCR, Bang-Andersen, B, Schiøtt, B, Chipot, C, Schoehn, G, Neyton, J, Dehez, F, Nury, H & Kristensen, AS 2024, 'Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT3 receptors', Nature Structural and Molecular Biology. https://doi.org/10.1038/s41594-024-01282-x

APA

López-Sánchez, U., Munro, L. J., Ladefoged, L. K., Pedersen, A. J., Brun, C. C., Lyngby, S. M., Baud, D., Juillan-Binard, C., Pedersen, M. G., Lummis, S. C. R., Bang-Andersen, B., Schiøtt, B., Chipot, C., Schoehn, G., Neyton, J., Dehez, F., Nury, H., & Kristensen, A. S. (Accepteret/In press). Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT3 receptors. Nature Structural and Molecular Biology. https://doi.org/10.1038/s41594-024-01282-x

Vancouver

López-Sánchez U, Munro LJ, Ladefoged LK, Pedersen AJ, Brun CC, Lyngby SM o.a. Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT3 receptors. Nature Structural and Molecular Biology. 2024. https://doi.org/10.1038/s41594-024-01282-x

Author

López-Sánchez, Uriel ; Munro, Lachlan Jake ; Ladefoged, Lucy Kate ; Pedersen, Anders Juel ; Brun, Christian Colding ; Lyngby, Signe Meisner ; Baud, Delphine ; Juillan-Binard, Céline ; Pedersen, Miriam Grønborg ; Lummis, Sarah C.R. ; Bang-Andersen, Benny ; Schiøtt, Birgit ; Chipot, Christophe ; Schoehn, Guy ; Neyton, Jacques ; Dehez, Francois ; Nury, Hugues ; Kristensen, Anders S. / Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT3 receptors. I: Nature Structural and Molecular Biology. 2024.

Bibtex

@article{a4f6b6e444084c898df071c21249a51a,
title = "Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT3 receptors",
abstract = "Vortioxetine (VTX) is a recently approved antidepressant that targets a variety of serotonin receptors. Here, we investigate the drug{\textquoteright}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.",
author = "Uriel L{\'o}pez-S{\'a}nchez and Munro, {Lachlan Jake} and Ladefoged, {Lucy Kate} and Pedersen, {Anders Juel} and Brun, {Christian Colding} and Lyngby, {Signe Meisner} and Delphine Baud and C{\'e}line Juillan-Binard and Pedersen, {Miriam Gr{\o}nborg} and Lummis, {Sarah C.R.} and Benny Bang-Andersen and Birgit Schi{\o}tt and Christophe Chipot and Guy Schoehn and Jacques Neyton and Francois Dehez and Hugues Nury and Kristensen, {Anders S.}",
note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.",
year = "2024",
doi = "10.1038/s41594-024-01282-x",
language = "English",
journal = "Nature Structural and Molecular Biology",
issn = "1545-9993",
publisher = "nature publishing group",

}

RIS

TY - JOUR

T1 - Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT3 receptors

AU - López-Sánchez, Uriel

AU - Munro, Lachlan Jake

AU - Ladefoged, Lucy Kate

AU - Pedersen, Anders Juel

AU - Brun, Christian Colding

AU - Lyngby, Signe Meisner

AU - Baud, Delphine

AU - Juillan-Binard, Céline

AU - Pedersen, Miriam Grønborg

AU - Lummis, Sarah C.R.

AU - Bang-Andersen, Benny

AU - Schiøtt, Birgit

AU - Chipot, Christophe

AU - Schoehn, Guy

AU - Neyton, Jacques

AU - Dehez, Francois

AU - Nury, Hugues

AU - Kristensen, Anders S.

N1 - Publisher Copyright: © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

U2 - 10.1038/s41594-024-01282-x

DO - 10.1038/s41594-024-01282-x

M3 - Journal article

C2 - 38698207

AN - SCOPUS:85191981558

JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

SN - 1545-9993

ER -

ID: 391501390