The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter. / Plenge, Per; Yang, Dongxue; Salomon, Kristine; Laursen, Louise; Kalenderoglou, Iris E.; Newman, Amy H.; Gouaux, Eric; Coleman, Jonathan A.; Loland, Claus J.

In: Nature Communications, Vol. 12, No. 1, 5063, 2021.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Plenge, P, Yang, D, Salomon, K, Laursen, L, Kalenderoglou, IE, Newman, AH, Gouaux, E, Coleman, JA & Loland, CJ 2021, 'The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter', Nature Communications, vol. 12, no. 1, 5063. https://doi.org/10.1038/s41467-021-25363-3

APA

Plenge, P., Yang, D., Salomon, K., Laursen, L., Kalenderoglou, I. E., Newman, A. H., Gouaux, E., Coleman, J. A., & Loland, C. J. (2021). The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter. Nature Communications, 12(1), [5063]. https://doi.org/10.1038/s41467-021-25363-3

Vancouver

Plenge P, Yang D, Salomon K, Laursen L, Kalenderoglou IE, Newman AH et al. The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter. Nature Communications. 2021;12(1). 5063. https://doi.org/10.1038/s41467-021-25363-3

Author

Plenge, Per ; Yang, Dongxue ; Salomon, Kristine ; Laursen, Louise ; Kalenderoglou, Iris E. ; Newman, Amy H. ; Gouaux, Eric ; Coleman, Jonathan A. ; Loland, Claus J. / The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter. In: Nature Communications. 2021 ; Vol. 12, No. 1.

Bibtex

@article{bc6ea6a0c5034ca89f7a25eb1cc0d488,
title = "The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter",
abstract = "Depression is a common mental disorder. The standard medical treatment is the selective serotonin reuptake inhibitors (SSRIs). All characterized SSRIs are competitive inhibitors of the serotonin transporter (SERT). A non-competitive inhibitor may produce a more favorable therapeutic profile. Vilazodone is an antidepressant with limited information on its molecular interactions with SERT. Here we use molecular pharmacology and cryo-EM structural elucidation to characterize vilazodone binding to SERT. We find that it exhibits non-competitive inhibition of serotonin uptake and impedes dissociation of [H-3]imipramine at low nanomolar concentrations. Our SERT structure with bound imipramine and vilazodone reveals a unique binding pocket for vilazodone, expanding the boundaries of the extracellular vestibule. Characterization of the binding site is substantiated with molecular dynamics simulations and systematic mutagenesis of interacting residues resulting in decreased vilazodone binding to the allosteric site. Our findings underline the versatility of SERT allosteric ligands and describe the unique binding characteristics of vilazodone.Vilazodone (VLZ) is a drug for the treatment of major depressive disorders that targets the serotonin transporter (SERT). Here, the authors combine pharmacology measurements and cryo-EM structural analysis to characterize VLZ binding to SERT and observe that VLZ exhibits non-competitive inhibition of serotonin transport and binds with nanomolar affinity to an allosteric site in SERT.",
keywords = "HIGH-AFFINITY RECOGNITION, CRYO-EM STRUCTURE, X-RAY STRUCTURES, NEUROTRANSMITTER TRANSPORTERS, DOPAMINE TRANSPORTER, MOLECULAR-DYNAMICS, BACTERIAL HOMOLOG, BINDING-SITE, FORCE-FIELD, OPEN-LABEL",
author = "Per Plenge and Dongxue Yang and Kristine Salomon and Louise Laursen and Kalenderoglou, {Iris E.} and Newman, {Amy H.} and Eric Gouaux and Coleman, {Jonathan A.} and Loland, {Claus J.}",
year = "2021",
doi = "10.1038/s41467-021-25363-3",
language = "English",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "nature publishing group",
number = "1",

}

RIS

TY - JOUR

T1 - The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter

AU - Plenge, Per

AU - Yang, Dongxue

AU - Salomon, Kristine

AU - Laursen, Louise

AU - Kalenderoglou, Iris E.

AU - Newman, Amy H.

AU - Gouaux, Eric

AU - Coleman, Jonathan A.

AU - Loland, Claus J.

PY - 2021

Y1 - 2021

N2 - Depression is a common mental disorder. The standard medical treatment is the selective serotonin reuptake inhibitors (SSRIs). All characterized SSRIs are competitive inhibitors of the serotonin transporter (SERT). A non-competitive inhibitor may produce a more favorable therapeutic profile. Vilazodone is an antidepressant with limited information on its molecular interactions with SERT. Here we use molecular pharmacology and cryo-EM structural elucidation to characterize vilazodone binding to SERT. We find that it exhibits non-competitive inhibition of serotonin uptake and impedes dissociation of [H-3]imipramine at low nanomolar concentrations. Our SERT structure with bound imipramine and vilazodone reveals a unique binding pocket for vilazodone, expanding the boundaries of the extracellular vestibule. Characterization of the binding site is substantiated with molecular dynamics simulations and systematic mutagenesis of interacting residues resulting in decreased vilazodone binding to the allosteric site. Our findings underline the versatility of SERT allosteric ligands and describe the unique binding characteristics of vilazodone.Vilazodone (VLZ) is a drug for the treatment of major depressive disorders that targets the serotonin transporter (SERT). Here, the authors combine pharmacology measurements and cryo-EM structural analysis to characterize VLZ binding to SERT and observe that VLZ exhibits non-competitive inhibition of serotonin transport and binds with nanomolar affinity to an allosteric site in SERT.

AB - Depression is a common mental disorder. The standard medical treatment is the selective serotonin reuptake inhibitors (SSRIs). All characterized SSRIs are competitive inhibitors of the serotonin transporter (SERT). A non-competitive inhibitor may produce a more favorable therapeutic profile. Vilazodone is an antidepressant with limited information on its molecular interactions with SERT. Here we use molecular pharmacology and cryo-EM structural elucidation to characterize vilazodone binding to SERT. We find that it exhibits non-competitive inhibition of serotonin uptake and impedes dissociation of [H-3]imipramine at low nanomolar concentrations. Our SERT structure with bound imipramine and vilazodone reveals a unique binding pocket for vilazodone, expanding the boundaries of the extracellular vestibule. Characterization of the binding site is substantiated with molecular dynamics simulations and systematic mutagenesis of interacting residues resulting in decreased vilazodone binding to the allosteric site. Our findings underline the versatility of SERT allosteric ligands and describe the unique binding characteristics of vilazodone.Vilazodone (VLZ) is a drug for the treatment of major depressive disorders that targets the serotonin transporter (SERT). Here, the authors combine pharmacology measurements and cryo-EM structural analysis to characterize VLZ binding to SERT and observe that VLZ exhibits non-competitive inhibition of serotonin transport and binds with nanomolar affinity to an allosteric site in SERT.

KW - HIGH-AFFINITY RECOGNITION

KW - CRYO-EM STRUCTURE

KW - X-RAY STRUCTURES

KW - NEUROTRANSMITTER TRANSPORTERS

KW - DOPAMINE TRANSPORTER

KW - MOLECULAR-DYNAMICS

KW - BACTERIAL HOMOLOG

KW - BINDING-SITE

KW - FORCE-FIELD

KW - OPEN-LABEL

U2 - 10.1038/s41467-021-25363-3

DO - 10.1038/s41467-021-25363-3

M3 - Journal article

C2 - 34417466

VL - 12

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 5063

ER -

ID: 277224975