A Salt Bridge Linking the First Intracellular Loop with the C Terminus Facilitates the Folding of the Serotonin Transporter

Koban, Florian; El‐Kasaby, Ali; Häusler, Cornelia; Stockner, Thomas; Simbrunner, Benedikt; Sitte, Harald H.; Freissmuth, Michael; Sučić, Sonja

doi:10.1074/jbc.m115.641357

Cited by 42 publications

(59 citation statements)

References 48 publications

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“…1), including part of the recognition sequence for SEC24C 32,33 . Despite the medium resolution of the diffraction data, the electron density features in the central site are of sufficient quality to allow us to position paroxetine.…”

Section: Resultsmentioning

confidence: 99%

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

Coleman

Gouaux

2018

Nat Struct Mol Biol

117

118

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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.

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Section: Resultsmentioning

confidence: 99%

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

Coleman

Gouaux

2018

Nat Struct Mol Biol

117

118

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“…The best three models, selected according to the DOPE score42, were inserted into a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine containing membrane using the membed procedure43. The membrane was pre-equilibrated to contain the SERT transporter44. The system was electroneutralized and 150 mM NaCl were added.…”

Section: Methodsmentioning

confidence: 99%

Direct PIP2 binding mediates stable oligomer formation of the serotonin transporter

et al. 2017

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The human serotonin transporter (hSERT) mediates uptake of serotonin from the synaptic cleft and thereby terminates serotonergic signalling. We have previously found by singlemolecule microscopy that SERT forms stable higher-order oligomers of differing stoichiometry at the plasma membrane of living cells. Here, we report that SERT oligomer assembly at the endoplasmic reticulum (ER) membrane follows a dynamic equilibration process, characterized by rapid exchange of subunits between different oligomers, and by a concentration dependence of the degree of oligomerization. After trafficking to the plasma membrane, however, the SERT stoichiometry is fixed. Stabilization of the oligomeric SERT complexes is mediated by the direct binding to phosphoinositide phosphatidylinositol-4,5-biphosphate (PIP 2 ). The observed spatial decoupling of oligomer formation from the site of oligomer operation provides cells with the ability to define protein quaternary structures independent of protein density at the cell surface.

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“…5e). Glu615 is thought to form a salt bridge with Arg152 in IL1 49 , but no side chain density is present which makes assignment of C-terminal register not possible. We hypothesize that the disorder of the C-terminus is due to dynamic properties, perhaps related to its importance in trafficking 50 .…”

Section: Intracellular Surface and C-terminal Hingementioning

confidence: 99%

X-ray structures and mechanism of the human serotonin transporter

Coleman

Green

Gouaux

2016

Nature

526

744

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The serotonin transporter (SERT) terminates serotonergic signaling through the sodium and chloride dependent reuptake of neurotransmitter into presynaptic neurons. SERT is a target for antidepressant and psychostimulant drugs, which block reuptake and prolong neurotransmitter signaling. Here we report x-ray crystallographic structures of human SERT at 3.15 Å resolution bound to the antidepressants (S)-citalopram or paroxetine. Antidepressants lock SERT in an outward-open conformation by lodging in the central binding site, located between transmembrane helices 1, 3, 6, 8, and 10, directly blocking serotonin binding. We further identify the location of an allosteric site in the complex as residing at the periphery of the extracellular vestibule, interposed between extracellular loops 4 and 6 and TMs 1, 6, 10, and 11. Occupancy of the allosteric site sterically hinders ligand unbinding from the central site, providing an explanation for the action of (S)-citalopram as an allosteric ligand. These structures define the mechanism of antidepressant action in SERT and provide blueprints for future drug design.

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A Salt Bridge Linking the First Intracellular Loop with the C Terminus Facilitates the Folding of the Serotonin Transporter

Cited by 42 publications

References 48 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

Direct PIP2 binding mediates stable oligomer formation of the serotonin transporter

X-ray structures and mechanism of the human serotonin transporter

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