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- EMDB-26160: Structure of human serotonin transporter bound to small molecule ... -

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Basic information

Entry
Database: EMDB / ID: EMD-26160
TitleStructure of human serotonin transporter bound to small molecule '8090 in lipid nanodisc and NaCl
Map data
Sample
  • Complex: Human serotonin transporter in complex with Fab15B8 bound to '8090 in NaCl
    • Complex: Sodium-dependent serotonin transporter
      • Protein or peptide: Sodium-dependent serotonin transporter
    • Complex: Fab15B8 heavy chain
      • Protein or peptide: 15B8 Fab heavy chain
    • Complex: Fab15B8 light chain
      • Protein or peptide: 15B8 Fab light chain
  • Ligand: 1-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperazine
KeywordsNeurotransmitter transporter / small molecule / membrane protein / TRANSPORT PROTEIN
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 / serotonin:sodium:chloride symporter activity / sperm ejaculation / neurotransmitter transmembrane transporter activity / negative regulation of synaptic transmission, dopaminergic ...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 / serotonin:sodium:chloride symporter activity / sperm ejaculation / neurotransmitter transmembrane transporter activity / negative regulation of synaptic transmission, dopaminergic / monoamine transmembrane transporter activity / serotonin uptake / monoamine transport / enteric nervous system development / negative regulation of organ growth / cellular response to cGMP / sodium ion binding / serotonin binding / neurotransmitter transport / vasoconstriction / brain morphogenesis / antiporter activity / syntaxin-1 binding / nitric-oxide synthase binding / social behavior / membrane depolarization / negative regulation of neuron differentiation / sodium ion transmembrane transport / endomembrane system / positive regulation of cell cycle / monoatomic cation channel activity / cellular response to retinoic acid / response to nutrient / memory / response to toxic substance / platelet aggregation / circadian rhythm / actin filament binding / integrin binding / response to estradiol / presynaptic membrane / postsynaptic membrane / response to hypoxia / endosome membrane / neuron projection / response to xenobiotic stimulus / membrane raft / focal adhesion / synapse / positive regulation of gene expression / 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
Sodium-dependent serotonin transporter
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsSingh I / Seth A
Funding support United States, 1 items
OrganizationGrant numberCountry
Department of Defense (DOD, United States)HR0011-19-2-0020 United States
CitationJournal: Cell / Year: 2023
Title: Structure-based discovery of conformationally selective inhibitors of the serotonin transporter.
Authors: Isha Singh / Anubha Seth / Christian B Billesbølle / Joao Braz / Ramona M Rodriguiz / Kasturi Roy / Bethlehem Bekele / Veronica Craik / Xi-Ping Huang / Danila Boytsov / Vladimir M Pogorelov ...Authors: Isha Singh / Anubha Seth / Christian B Billesbølle / Joao Braz / Ramona M Rodriguiz / Kasturi Roy / Bethlehem Bekele / Veronica Craik / Xi-Ping Huang / Danila Boytsov / Vladimir M Pogorelov / Parnian Lak / Henry O'Donnell / Walter Sandtner / John J Irwin / Bryan L Roth / Allan I Basbaum / William C Wetsel / Aashish Manglik / Brian K Shoichet / Gary Rudnick /
Abstract: The serotonin transporter (SERT) removes synaptic serotonin and is the target of anti-depressant drugs. SERT adopts three conformations: outward-open, occluded, and inward-open. All known inhibitors ...The serotonin transporter (SERT) removes synaptic serotonin and is the target of anti-depressant drugs. SERT adopts three conformations: outward-open, occluded, and inward-open. All known inhibitors target the outward-open state except ibogaine, which has unusual anti-depressant and substance-withdrawal effects, and stabilizes the inward-open conformation. Unfortunately, ibogaine's promiscuity and cardiotoxicity limit the understanding of inward-open state ligands. We docked over 200 million small molecules against the inward-open state of the SERT. Thirty-six top-ranking compounds were synthesized, and thirteen inhibited; further structure-based optimization led to the selection of two potent (low nanomolar) inhibitors. These stabilized an outward-closed state of the SERT with little activity against common off-targets. A cryo-EM structure of one of these bound to the SERT confirmed the predicted geometry. In mouse behavioral assays, both compounds had anxiolytic- and anti-depressant-like activity, with potencies up to 200-fold better than fluoxetine (Prozac), and one substantially reversed morphine withdrawal effects.
History
DepositionFeb 9, 2022-
Header (metadata) releaseMar 15, 2023-
Map releaseMar 15, 2023-
UpdateMar 27, 2024-
Current statusMar 27, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26160.png

Downloads & links

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Map

FileDownload / File: emd_26160.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.81 Å
Density
Contour LevelBy AUTHOR: 0.102
Minimum - Maximum-0.29407343 - 0.61150277
Average (Standard dev.)0.00024178246 (±0.012124147)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 291.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Human serotonin transporter in complex with Fab15B8 bound to '809...

EntireName: Human serotonin transporter in complex with Fab15B8 bound to '8090 in NaCl
Components
  • Complex: Human serotonin transporter in complex with Fab15B8 bound to '8090 in NaCl
    • Complex: Sodium-dependent serotonin transporter
      • Protein or peptide: Sodium-dependent serotonin transporter
    • Complex: Fab15B8 heavy chain
      • Protein or peptide: 15B8 Fab heavy chain
    • Complex: Fab15B8 light chain
      • Protein or peptide: 15B8 Fab light chain
  • Ligand: 1-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperazine

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Supramolecule #1: Human serotonin transporter in complex with Fab15B8 bound to '809...

SupramoleculeName: Human serotonin transporter in complex with Fab15B8 bound to '8090 in NaCl
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3

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Supramolecule #2: Sodium-dependent serotonin transporter

SupramoleculeName: Sodium-dependent serotonin transporter / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Fab15B8 heavy chain

SupramoleculeName: Fab15B8 heavy chain / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)

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Supramolecule #4: Fab15B8 light chain

SupramoleculeName: Fab15B8 light chain / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: 15B8 Fab heavy chain

MacromoleculeName: 15B8 Fab heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 13.166742 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QVQLQQSGPE LVKLGASVRI SCKASGYRFS YSWMNWVKQR PGKGLEWIGR IYPGDGDTKY SGKFKGKATL TADKSSSTVY MQLSSLTSE DSAVYFCARS AYGSEGFAMD YWGQGTSVTV S

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Macromolecule #2: 15B8 Fab light chain

MacromoleculeName: 15B8 Fab light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 11.905246 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
DIVLTQSPAS LAVSLGQRAT ISCRASESVD NYGISFLNWF QQKPGQPPKL LIYAASNQGS GVPARFSGSG SGTYFSLNIH PMEEDDTAV YFCQQTKGVS WTFGGGTKVE IK

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Macromolecule #3: Sodium-dependent serotonin transporter

MacromoleculeName: Sodium-dependent serotonin transporter / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 61.062129 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GERETWGKKV DFLLSVIGYA VDLGNVWRFP YICYQNGGGA FLLPYTIMAI FGGIPLFYME LALGQYHRNG CISIWRKICP IFKGIGYAI CIIAFYIASY YNTIMAWALY YLISSFTDQL PWTSCKNSWN TGNCTNYFSE DNITWTLHST SPAEEFYTRH V LQIHRSKG ...String:
GERETWGKKV DFLLSVIGYA VDLGNVWRFP YICYQNGGGA FLLPYTIMAI FGGIPLFYME LALGQYHRNG CISIWRKICP IFKGIGYAI CIIAFYIASY YNTIMAWALY YLISSFTDQL PWTSCKNSWN TGNCTNYFSE DNITWTLHST SPAEEFYTRH V LQIHRSKG LQDLGGISWQ LALCIMLIFT VIYFSIWKGV KTSGKVVWVT ATFPYIILSV LLVRGATLPG AWRGVLFYLK PN WQKLLET GVWIDAAAQI FFSLGPGFGV LLAFASYNKF NNNCYQDALV TSVVNCMTSF VSGFVIFTVL GYMAEMRNED VSE VAKDAG PSLLFITYAE AIANMPASTF FAIIFFLMLI TLGLDSTFAG LEGVITAVLD EFPHVWAKRR ERFVLAVVIT CFFG SLVTL TFGGAYVVKL LEEYATGPAV LTVALIEAVA VSWFYGITQF CRDVKEMLGF SPGWFWRICW VAISPLFLLF IICSF LMSP PQLRLFQYNY PYWSIILGYC IGTSSFICIP TYIAYRLIIT PGTFKERIIK SITPETP

UniProtKB: Sodium-dependent serotonin transporter

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Macromolecule #4: 1-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperazine

MacromoleculeName: 1-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperazine / type: ligand / ID: 4 / Number of copies: 1 / Formula: KWC
Molecular weightTheoretical: 263.334 Da
Chemical component information

ChemComp-KWC:
1-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperazine

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.1 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: Ab initio reconstruction
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.2.0)
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: cryoSPARC (ver. 3.2.0)
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.2.0) / Number images used: 187696

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