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- PDB-9hco: Outward-open structure of human serotonin transporter bound to vi... -

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Basic information

Entry
Database: PDB / ID: 9hco
TitleOutward-open structure of human serotonin transporter bound to vilazodone
Components
  • 15B8 Fab heavy chain
  • 15B8 Fab light chain
  • Sodium-dependent serotonin transporter
KeywordsMEMBRANE PROTEIN / Monoamine transporter / LeuT fold / antidepressant binding / Inhibitor complex
Function / homology
Function and homology information


negative regulation of cerebellar granule cell precursor proliferation / regulation of thalamus size / Serotonin clearance from the synaptic cleft / serotonergic synapse / positive regulation of serotonin secretion / cocaine binding / negative regulation of synaptic transmission, dopaminergic / serotonin:sodium:chloride symporter activity / cellular response to cGMP / negative regulation of organ growth ...negative regulation of cerebellar granule cell precursor proliferation / regulation of thalamus size / Serotonin clearance from the synaptic cleft / serotonergic synapse / positive regulation of serotonin secretion / cocaine binding / negative regulation of synaptic transmission, dopaminergic / serotonin:sodium:chloride symporter activity / cellular response to cGMP / negative regulation of organ growth / sodium ion binding / serotonin uptake / neurotransmitter transmembrane transporter activity / vasoconstriction / enteric nervous system development / monoamine transmembrane transporter activity / : / serotonin binding / brain morphogenesis / antiporter activity / syntaxin-1 binding / negative regulation of neuron differentiation / male mating behavior / neurotransmitter transport / amino acid transport / nitric-oxide synthase binding / conditioned place preference / membrane depolarization / monoatomic cation channel activity / cellular response to retinoic acid / behavioral response to cocaine / positive regulation of cell cycle / endomembrane system / response to nutrient / sodium ion transmembrane transport / circadian rhythm / platelet aggregation / integrin binding / response to toxic substance / memory / actin filament binding / response to estradiol / presynaptic membrane / response to hypoxia / postsynaptic membrane / endosome membrane / neuron projection / membrane raft / response to xenobiotic stimulus / focal adhesion / positive regulation of gene expression / synapse / identical protein binding / plasma membrane
Similarity search - Function
Sodium:neurotransmitter symporter, serotonin, N-terminal / Serotonin (5-HT) neurotransmitter transporter, N-terminus / Sodium:neurotransmitter symporter family signature 2. / Sodium:neurotransmitter symporter family signature 1. / Sodium:neurotransmitter symporter / Sodium:neurotransmitter symporter superfamily / Sodium:neurotransmitter symporter family / Sodium:neurotransmitter symporter family profile.
Similarity search - Domain/homology
Chem-YG7 / Sodium-dependent serotonin transporter
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.78 Å
AuthorsKalenderoglou, I.E. / Tillmann, P. / Loland, C.J.
Funding support Denmark, European Union, United States, 7items
OrganizationGrant numberCountry
Novo Nordisk FoundationNNF22OC0079091 Denmark
Independent Research Fund Denmark - Medical Sciences1030-00036B Denmark
H2020 Marie Curie Actions of the European Commission860954European Union
The Carlsberg Foundation1030-00036B Denmark
National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA)Z1A DA000389 United States
Novo Nordisk FoundationNNF17SA0024386 Denmark
Novo Nordisk FoundationNNF22OC0075808 Denmark
CitationJournal: Nat Commun / Year: 2025
Title: Structural basis of vilazodone dual binding mode to the serotonin transporter.
Authors: Iris E Kalenderoglou / Andreas Nygaard / Caleb D Vogt / Anton Turaev / Tillmann Pape / Nathan B P Adams / Amy Hauck Newman / Claus J Loland /
Abstract: The serotonin transporter (SERT) plays a pivotal role in regulating serotonin (5-HT) signaling and is a key target in the treatment of psychiatric disorders. SERT has a binding site (S1) for 5-HT ...The serotonin transporter (SERT) plays a pivotal role in regulating serotonin (5-HT) signaling and is a key target in the treatment of psychiatric disorders. SERT has a binding site (S1) for 5-HT that also serves as a high-affinity binding site for antidepressants. The antidepressant vilazodone has been shown to inhibit SERT by binding to an allosteric site. Here, we present the cryo-EM structure of SERT with vilazodone bound to the S1 site and extending towards the allosteric site. We systematically dissect the vilazodone molecule into fragments and find that the terminal indole ring is the key determinant of its high affinity to SERT. Further, unlike typical Na-dependent SERT-selective antidepressants, vilazodone exhibits a dissociation constant (K) for purified SERT in the nanomolar range both in the presence and absence of Na. We substantiate this binding mode by exploring the conformational impact of vilazodone binding to SERT using site-specific insertion of the fluorescent non-canonical amino acid Anap. Our results offer molecular insight into the distinct pharmacological profile of a clinically used polymodal antidepressant.
History
DepositionNov 11, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 17, 2025Provider: repository / Type: Initial release
Revision 1.0Sep 17, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Sep 17, 2025Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Sep 17, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Sodium-dependent serotonin transporter
H: 15B8 Fab heavy chain
L: 15B8 Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,7157
Polymers124,1923
Non-polymers5234
Water21612
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Sodium-dependent serotonin transporter / SERT / 5HT transporter / 5HTT / Solute carrier family 6 member 4


Mass: 76116.453 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: human SERT full length with GGS linker, thromvin site, GGS linker, twinII site, GGS linker and His12-tag
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC6A4, HTT, SERT / Plasmid: pFastBac
Details (production host): Baculovirus-derived vector with SLC6A4 gene insert
Cell line (production host): Expi293 / Production host: Homo sapiens (human) / Strain (production host): HEK293 / References: UniProt: P31645

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Antibody , 2 types, 2 molecules HL

#2: Antibody 15B8 Fab heavy chain


Mass: 24516.510 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Murine monoclonal antibody (15B8) specific for the human serotonin transporter (SERT)
Source: (gene. exp.) Mus musculus (house mouse) / Plasmid: pFastBac Dual
Details (production host): Baculovirus expression vector used in BacMam system for protein expression in Sf9 cells.
Cell (production host): Sf9 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
#3: Antibody 15B8 Fab light chain


Mass: 23558.977 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Murine monoclonal antibody (15B8) specific for the human serotonin transporter (SERT)
Source: (gene. exp.) Mus musculus (house mouse) / Plasmid: pFastBac Dual
Details (production host): Baculovirus expression vector used in BacMam system for protein expression in Sf9 cells.
Cell (production host): Sf9 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)

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Non-polymers , 4 types, 16 molecules

#4: Chemical ChemComp-YG7 / 5-{4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl}-1-benzofuran-2-carboxamide


Mass: 441.525 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H27N5O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#6: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 12 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Complex of the Serotonin Transporter with the antidepressant vilazodone
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Strain: HEK293 / Cell: Expi293 / Plasmid: pFastBac
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 20000 nm / Nominal defocus min: 6000 nm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 42 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON III (4k x 4k)

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Processing

EM software
IDNameVersionCategoryDetails (eV)
3EPU3.2image acquisitionIMAGE ACQUISITION
4cryoSPARC3.3.2 - 4.4.1image acquisitionPARTICLE SELECTION AND 3D RECONSTRUCTION
5Coot0.9.8.6image acquisitionREAL SPACE REFINEMENT
6UCSF ChimeraX1.8image acquisitionSTRUCTURE ALIGNMENT
7PHENIX1.21image acquisitionREAL SPACE REFINEMENT - VALIDATION - LIGAND PARAMETERIZATION
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.78 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 239223 / Symmetry type: POINT

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