Characterization of an allosteric citalopram‐binding site at the serotonin transporter

Chen, Fenghua; Larsen, Mads; Neubauer, Henrik Amtoft; Sanchéz, Connie; Plenge, Per; Wiborg, Ove

doi:10.1111/j.1471-4159.2004.02835.x

Cited by 97 publications

(78 citation statements)

References 39 publications

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“…Monoamine transporters have twelve transmembrane helices (TM) with TMs 1-5 and TMs 6-10 forming an invertedtopological repeat within which is a central binding site for substrate and ions approximately halfway across the membrane [7][8][9] . An extracellular vestibule in the outward-facing conformation 7,9,10 forms a secondary, allosteric site which, when occupied by ligands, can result in modulation of transporter activity by altering the kinetics of ligand dissociation from the central site [11][12][13] . Addictive substances such as cocaine and amphetamine bind to monoamine transporters and can either inhibit NT transport or promote NT efflux, respectively 14,15 .…”

Section: Main Textmentioning

confidence: 99%

“…It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/204859 doi: bioRxiv preprint first posted online Oct. 17, 2017; page 3 of 15 in modulation of transporter activity by altering the kinetics of ligand dissociation from the central site [11][12][13] . Addictive substances such as cocaine and amphetamine bind to monoamine transporters and can either inhibit NT transport or promote NT efflux, respectively 14,15 .…”

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Structural basis for recognition of diverse antidepressants by the human serotonin transporter

Coleman

Gouaux

2017

Preprint

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Selective serotonin reuptake inhibitors are clinically prescribed antidepressants that act by increasing the local concentration of neurotransmitter at synapses and in extracellular spaces via blockade of the serotonin transporter. Here we report x-ray structures of engineered thermostable variants of the human serotonin transporter bound to the antidepressants sertraline, fluvoxamine, and paroxetine. The drugs prevent serotonin binding by occupying the central substrate binding site and stabilizing the transporter in an outward-open conformation.These structures explain how residues within the central site orchestrate binding of chemically diverse inhibitors and mediate transporter-drug selectivity. MAIN TEXTIn the central nervous system the serotonin transporter (SERT) modulates serotoninergic signaling by carrying out the uptake of serotonin (5-HT) from the synaptic space into presynaptic . An extracellular vestibule in the outward-facing conformation 7,9,10 forms a secondary, allosteric site which, when occupied by ligands, can result . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/204859 doi: bioRxiv preprint first posted online Oct. 17, 2017; page 3 of 15 in modulation of transporter activity by altering the kinetics of ligand dissociation from the central site [11][12][13] . Addictive substances such as cocaine and amphetamine bind to monoamine transporters and can either inhibit NT transport or promote NT efflux, respectively 14,15 . Selective serotonin reuptake inhibitors (SSRIs) are a class of small molecules that are highly selective for SERT over DAT and NET and that inhibit 5-HT reuptake with nanomolar potency Fig. 1), and as a consequence these compounds bind with a range of affinities to SERT. Sertraline contains a tetrahydronaphthalene ring system linked to a secondary amine together with a meta and para substituted dichlorophenyl group. Fluvoxamine, by contrast, consists of a 2-aminoethyloxime moiety attached to a methyoxybutyl group, and a phenyl group containing a trifluoronated methyl at the para positon. Fluoxetine also contains a trifluoronated aromatic group but is instead coupled to a phenylpropylamine moiety. Paroxetine and citalopram also differ substantially in the structures of their aromatic, amine, and halogenated substitutents.Recently, we solved x-ray structures of a thermostabilized, transport-inactive construct of human SERT, deemed the ts3 construct, in complex with the SSRIs paroxetine and citalopram 8 .We employed the thermostabilized variant of SERT in order to facilitate purification and crystallization 19,20 . One of the thermostabilizing mutations, however, involves a residue (Thr439Ser) that is directly positioned within the central binding site, in close proximity to the bound SSRIs. Moreover, recent computational modeling of a wild-type SERT-paroxetine complex, in which the structure of the Drosophila DAT was used as a ...

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Section: Main Textmentioning

confidence: 99%

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confidence: 99%

Structural basis for recognition of diverse antidepressants by the human serotonin transporter

Coleman

Gouaux

2017

Preprint

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“…Selective blockers of SERT (citalopram, paroxetine, sertraline) bind to the domain of the serotonin transporter, which overlaps with the substrate binding site (Koe et al, 1990;Chen et al, 2005). Therefore, we used sertraline as a representative SERT-selective drug to study possible effects of SERT function inhibition on Tat neurotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Different effects of selective dopamine uptake inhibitors, GBR 12909 and WIN 35428, on HIV-1 Tat toxicity in rat fetal midbrain neurons

et al. 2008

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Drug abuse is a risk factor for neurological complications in HIV infection. Cocaine has been shown to exacerbate HIV-associated brain pathology and enhance neurotoxicity of HIV-1 Tat and gp120 proteins. In this study, we found that the selective inhibitor of dopamine transporter (DAT) function, 1-[2-[bis(4-fluorophenyl) methoxy]ethyl]-4-(3-phenylpropyl) piperazine (GBR 12909, vanoxerine), but not the selective inhibitors of serotonin and norepinephrine (SERT and NET) transporters, sertraline and nizoxetine, emulated cocaine-mediated enhancement of Tat neurotoxicity in rat fetal midbrain primary cell cultures. Similar to cocaine, the significant increase of Tat toxicity in midbrain cell cultures was observed at micromolar dose (5 μM) of GBR 12909. However, different doses of another selective dopamine uptake inhibitor, WIN 35428 did not affect Tat neurotoxicity. The study supports the hypothesis that changes in control of dopamine (DA) homeostasis are important for the cocaine-mediated enhancement of HIV-1 Tat neurotoxicity. Our results also demonstrate that the inhibitors of DA uptake, which can bind to different domains of DAT, differ in their ability to mimic synergistic toxicity of cocaine and HIV-1 Tat in the midbrain cell culture.

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“…84 Multimerization appears to be a requirement for proper trafficking of the transporter from the endoplasmic reticulum to the plasma membrane 82 rather than a prerequisite for substrate translocation. However, in the biogenic amine transporters, it may also be pertinent to the reported allosteric effect exhibited by some antidepressants 85,86 as well as to the mechanism of amphetamine-induced substrate efflux. 87 What is the oligomeric state of LeuT?…”

Section: Putative Oligomerizationmentioning

confidence: 99%

LeuT: A prokaryotic stepping stone on the way to a eukaryotic neurotransmitter transporter structure

Singh¹

2008

Channels

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To cite this article: Satinder K. Singh (2008) LeuT: A prokaryotic stepping stone on the way to a eukaryotic neurotransmitter transporter structure, Channels Ion-coupled secondary transport is utilized by a broad range of integral membrane proteins to catalyze the energetically unfavorable movement of solute molecules across a lipid bilayer. Members of the solute carrier 6 (SLC6) family, present in both prokaryotes and eukaryotes, are sodium-coupled symporters that play crucial roles in processes as diverse as nutrient uptake and neurotransmitter clearance. The crystal structure of LeuT, a bacterial member of this family, provided the first atomic-level glimpse into overall architecture, pinpointed the substrate and sodium binding sites and implicated candidate helices and residues in the "gating" conformational changes that accompany ion binding and release. The structure is consistent with a wealth of elegant biochemical data on the eukaryotic counterparts and has for the first time permitted the construction of accurate homology models that can be directly tested experimentally. Sequence identity is especially high near the substrate and sodium binding sites and, thus, molecular insights within these regions have been substantial. However, there are several topics relevant to transport mechanism, inhibition and regulation that structure/function studies of LeuT cannot adequately address, suggesting the need for a eukaryotic transporter crystal structure.

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Characterization of an allosteric citalopram‐binding site at the serotonin transporter

Cited by 97 publications

References 39 publications

Structural basis for recognition of diverse antidepressants by the human serotonin transporter

Structural basis for recognition of diverse antidepressants by the human serotonin transporter

Different effects of selective dopamine uptake inhibitors, GBR 12909 and WIN 35428, on HIV-1 Tat toxicity in rat fetal midbrain neurons

LeuT: A prokaryotic stepping stone on the way to a eukaryotic neurotransmitter transporter structure

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