Substrate and inhibitor binding to the serotonin transporter: Insights from computational, crystallographic, and functional studies

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Substrate and inhibitor binding to the serotonin transporter : Insights from computational, crystallographic, and functional studies. / Zeppelin, Talia; Ladefoged, Lucy Kate; Sinning, Steffen; Schiøtt, Birgit.

I: Neuropharmacology, 23.02.2019.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisReviewForskningpeer review

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@article{170d151aa2d746c09ee9d8245a8c16b0,
title = "Substrate and inhibitor binding to the serotonin transporter: Insights from computational, crystallographic, and functional studies",
abstract = "The serotonin transporter (SERT) belongs to the monoamine transporter family, which also includes the dopamine and norepinephrine transporters. SERT is essential for regulating serotonergic signaling by the reuptake of serotonin from the synaptic cleft back into the presynaptic neuron. Dysregulation of SERT has been implicated in several major psychiatric disorders such as major depressive disorder (MDD). MDD was among the top five leading causes of years lived with disease in 2016 and is characterized as a major global burden. Several drugs have been developed to target SERT for use in the treatment of MDD, and their respective binding modes and locations within SERT have been studied. The elucidation of the first structure of a bacterial SERT homologue in 2005 has accelerated crystallographic, computational, and functional studies to further elucidate drug binding and method of action in SERT. Herein, we aim to highlight and compare these studies with an emphasis on what the different experimental methods conclude on substrate and inhibitor binding modes, and the potential caveats of using the different types of studies are discussed. We focus this review on the binding of cognate substrate and drugs belonging to the different families of antidepressants, including tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and multimodal drugs, as well as illicit drugs such as cocaine, amphetamines, and ibogaine.",
author = "Talia Zeppelin and Ladefoged, {Lucy Kate} and Steffen Sinning and Birgit Schi{\o}tt",
note = "Copyright {\circledC} 2019 Elsevier Ltd. All rights reserved.",
year = "2019",
month = "2",
day = "23",
doi = "10.1016/j.neuropharm.2019.02.030",
language = "English",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Pergamon Press",

}

RIS

TY - JOUR

T1 - Substrate and inhibitor binding to the serotonin transporter

T2 - Insights from computational, crystallographic, and functional studies

AU - Zeppelin, Talia

AU - Ladefoged, Lucy Kate

AU - Sinning, Steffen

AU - Schiøtt, Birgit

N1 - Copyright © 2019 Elsevier Ltd. All rights reserved.

PY - 2019/2/23

Y1 - 2019/2/23

N2 - The serotonin transporter (SERT) belongs to the monoamine transporter family, which also includes the dopamine and norepinephrine transporters. SERT is essential for regulating serotonergic signaling by the reuptake of serotonin from the synaptic cleft back into the presynaptic neuron. Dysregulation of SERT has been implicated in several major psychiatric disorders such as major depressive disorder (MDD). MDD was among the top five leading causes of years lived with disease in 2016 and is characterized as a major global burden. Several drugs have been developed to target SERT for use in the treatment of MDD, and their respective binding modes and locations within SERT have been studied. The elucidation of the first structure of a bacterial SERT homologue in 2005 has accelerated crystallographic, computational, and functional studies to further elucidate drug binding and method of action in SERT. Herein, we aim to highlight and compare these studies with an emphasis on what the different experimental methods conclude on substrate and inhibitor binding modes, and the potential caveats of using the different types of studies are discussed. We focus this review on the binding of cognate substrate and drugs belonging to the different families of antidepressants, including tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and multimodal drugs, as well as illicit drugs such as cocaine, amphetamines, and ibogaine.

AB - The serotonin transporter (SERT) belongs to the monoamine transporter family, which also includes the dopamine and norepinephrine transporters. SERT is essential for regulating serotonergic signaling by the reuptake of serotonin from the synaptic cleft back into the presynaptic neuron. Dysregulation of SERT has been implicated in several major psychiatric disorders such as major depressive disorder (MDD). MDD was among the top five leading causes of years lived with disease in 2016 and is characterized as a major global burden. Several drugs have been developed to target SERT for use in the treatment of MDD, and their respective binding modes and locations within SERT have been studied. The elucidation of the first structure of a bacterial SERT homologue in 2005 has accelerated crystallographic, computational, and functional studies to further elucidate drug binding and method of action in SERT. Herein, we aim to highlight and compare these studies with an emphasis on what the different experimental methods conclude on substrate and inhibitor binding modes, and the potential caveats of using the different types of studies are discussed. We focus this review on the binding of cognate substrate and drugs belonging to the different families of antidepressants, including tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and multimodal drugs, as well as illicit drugs such as cocaine, amphetamines, and ibogaine.

U2 - 10.1016/j.neuropharm.2019.02.030

DO - 10.1016/j.neuropharm.2019.02.030

M3 - Review

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -