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- EMDB-23365: 5-HT bound serotonin transporter reconstituted in lipid nanodisc ... -

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Basic information

Entry
Database: EMDB / ID: EMD-23365
Title5-HT bound serotonin transporter reconstituted in lipid nanodisc in presence of NaCl in outward facing conformation
Map data
Sample
  • Complex: human serotonin transporter in complex with 15B8 Fab in presence of serotonin in NaCl
    • Protein or peptide: Sodium-dependent serotonin transporter
    • Protein or peptide: variable domain of 15B8 antibody Fab heavy chain
    • Protein or peptide: variable domain of 15B8 antibody Fab light chain
  • Ligand: SEROTONIN
  • Ligand: CHLORIDE ION
  • Ligand: SODIUM ION
  • Ligand: DECANE
  • Ligand: HEPTANE
  • Ligand: PENTANE
  • Ligand: CHOLESTEROL
Keywordsserotonin / outward open / serotonin transporter / Fab / MEMBRANE 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 / negative regulation of synaptic transmission, dopaminergic / sperm ejaculation / serotonin:sodium:chloride symporter activity / cellular response to cGMP ...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 / sperm ejaculation / serotonin:sodium:chloride symporter activity / cellular response to cGMP / enteric nervous system development / sodium ion binding / negative regulation of organ growth / serotonin uptake / neurotransmitter transmembrane transporter activity / monoamine transmembrane transporter activity / serotonin binding / monoamine transport / conditioned place preference / vasoconstriction / brain morphogenesis / neurotransmitter transport / syntaxin-1 binding / antiporter activity / amino acid transport / nitric-oxide synthase binding / behavioral response to cocaine / membrane depolarization / social behavior / negative regulation of neuron differentiation / endomembrane system / positive regulation of cell cycle / sodium ion transmembrane transport / monoatomic cation channel activity / cellular response to retinoic acid / response to nutrient / platelet aggregation / memory / response to toxic substance / 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: 3.3 Å
AuthorsYang D / Gouaux E
Funding support United States, 2 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
National Institutes of Health/National Institute of Mental Health (NIH/NIMH) United States
CitationJournal: Sci Adv / Year: 2021
Title: Illumination of serotonin transporter mechanism and role of the allosteric site.
Authors: Dongxue Yang / Eric Gouaux /
Abstract: The serotonin transporter (SERT) terminates serotonin signaling by using sodium and chloride gradients to drive reuptake of serotonin into presynaptic neurons and is the target of widely used ...The serotonin transporter (SERT) terminates serotonin signaling by using sodium and chloride gradients to drive reuptake of serotonin into presynaptic neurons and is the target of widely used medications to treat neuropsychiatric disorders. Despite decades of study, the molecular mechanism of serotonin transport, the coupling to ion gradients, and the role of the allosteric site have remained elusive. Here, we present cryo–electron microscopy structures of SERT in serotonin-bound and serotonin-free states, in the presence of sodium or potassium, resolving all fundamental states of the transport cycle. From the SERT-serotonin complex, we localize the substrate-bound allosteric site, formed by an aromatic pocket positioned in the scaffold domain in the extracellular vestibule, connected to the central site via a short tunnel. Together with elucidation of multiple apo state conformations, we provide previously unseen structural understanding of allosteric modulation, demonstrating how SERT binds serotonin from synaptic volumes and promotes unbinding into the presynaptic neurons.
History
DepositionJan 26, 2021-
Header (metadata) releaseDec 15, 2021-
Map releaseDec 15, 2021-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.3
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.3
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7lia
  • Surface level: 0.3
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23365.png

Downloads & links

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Map

FileDownload / File: emd_23365.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 400 pix.
= 259.2 Å		0.65 Å/pix.
x 400 pix.
= 259.2 Å		0.65 Å/pix.
x 400 pix.
= 259.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.648 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2 / Movie #1: 0.3
Minimum - Maximum-3.5383763 - 4.4436874
Average (Standard dev.)0.00092184526 (±0.067610726)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 259.2 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.6480.6480.648
M x/y/z400400400
origin x/y/z0.0000.0000.000
length x/y/z259.200259.200259.200
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ450450450
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS400400400
D min/max/mean-3.5384.4440.001

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Supplemental data

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Additional map: #1

Fileemd_23365_additional_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human serotonin transporter in complex with 15B8 Fab in presence ...

EntireName: human serotonin transporter in complex with 15B8 Fab in presence of serotonin in NaCl
Components
  • Complex: human serotonin transporter in complex with 15B8 Fab in presence of serotonin in NaCl
    • Protein or peptide: Sodium-dependent serotonin transporter
    • Protein or peptide: variable domain of 15B8 antibody Fab heavy chain
    • Protein or peptide: variable domain of 15B8 antibody Fab light chain
  • Ligand: SEROTONIN
  • Ligand: CHLORIDE ION
  • Ligand: SODIUM ION
  • Ligand: DECANE
  • Ligand: HEPTANE
  • Ligand: PENTANE
  • Ligand: CHOLESTEROL

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Supramolecule #1: human serotonin transporter in complex with 15B8 Fab in presence ...

SupramoleculeName: human serotonin transporter in complex with 15B8 Fab in presence of serotonin in NaCl
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Sodium-dependent serotonin transporter

MacromoleculeName: Sodium-dependent serotonin transporter / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 60.875957 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: RETWGKKVDF LLSVIGYAVD LGNVWRFPYI CYQNGGGAFL LPYTIMAIFG GIPLFYMELA LGQYHRNGCI SIWRKICPIF KGIGYAICI IAFYIASYYN TIMAWALYYL ISSFTDQLPW TSCKNSWNTG NCTNYFSEDN ITWTLHSTSP AEEFYTRHVL Q IHRSKGLQ ...String:
RETWGKKVDF LLSVIGYAVD LGNVWRFPYI CYQNGGGAFL LPYTIMAIFG GIPLFYMELA LGQYHRNGCI SIWRKICPIF KGIGYAICI IAFYIASYYN TIMAWALYYL ISSFTDQLPW TSCKNSWNTG NCTNYFSEDN ITWTLHSTSP AEEFYTRHVL Q IHRSKGLQ DLGGISWQLA LCIMLIFTVI YFSIWKGVKT SGKVVWVTAT FPYIILSVLL VRGATLPGAW RGVLFYLKPN WQ KLLETGV WIDAAAQIFF SLGPGFGVLL AFASYNKFNN NCYQDALVTS VVNCMTSFVS GFVIFTVLGY MAEMRNEDVS EVA KDAGPS LLFITYAEAI ANMPASTFFA IIFFLMLITL GLDSTFAGLE GVITAVLDEF PHVWAKRRER FVLAVVITCF FGSL VTLTF GGAYVVKLLE EYATGPAVLT VALIEAVAVS WFYGITQFCR DVKEMLGFSP GWFWRICWVA ISPLFLLFII CSFLM SPPQ LRLFQYNYPY WSIILGYCIG TSSFICIPTY IAYRLIITPG TFKERIIKSI TPETP

UniProtKB: Sodium-dependent serotonin transporter

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Macromolecule #2: variable domain of 15B8 antibody Fab heavy chain

MacromoleculeName: variable domain of 15B8 antibody Fab heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 12.980533 KDa
SequenceString:
QVQLQQSGPE LVKLGASVRI SCKASGYRFS YSWMNWVKQR PGKGLEWIGR IYPGDGDTKY SGKFKGKATL TADKSSSTVY MQLSSLTSE DSAVYFCARS AYGSEGFAMD YWGQGTSVT

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Macromolecule #3: variable domain of 15B8 antibody Fab light chain

MacromoleculeName: variable domain of 15B8 antibody Fab light chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 11.776065 KDa
SequenceString:
DIVLTQSPAS LAVSLGQRAT ISCRASESVD NYGISFLNWF QQKPGQPPKL LIYAASNQGS GVPARFSGSG SGTYFSLNIH PMEEDDTAV YFCQQTKGVS WTFGGGTKVE I

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Macromolecule #5: SEROTONIN

MacromoleculeName: SEROTONIN / type: ligand / ID: 5 / Number of copies: 2 / Formula: SRO
Molecular weightTheoretical: 176.215 Da
Chemical component information

ChemComp-SRO:
SEROTONIN / neurotransmitter*YM

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Macromolecule #6: CHLORIDE ION

MacromoleculeName: CHLORIDE ION / type: ligand / ID: 6 / Number of copies: 1 / Formula: CL
Molecular weightTheoretical: 35.453 Da

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Macromolecule #7: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 7 / Number of copies: 2
Molecular weightTheoretical: 22.99 Da

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Macromolecule #8: DECANE

MacromoleculeName: DECANE / type: ligand / ID: 8 / Number of copies: 5 / Formula: D10
Molecular weightTheoretical: 142.282 Da
Chemical component information

ChemComp-D10:
DECANE

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Macromolecule #9: HEPTANE

MacromoleculeName: HEPTANE / type: ligand / ID: 9 / Number of copies: 13 / Formula: HP6
Molecular weightTheoretical: 100.202 Da
Chemical component information

ChemComp-HP6:
HEPTANE

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Macromolecule #10: PENTANE

MacromoleculeName: PENTANE / type: ligand / ID: 10 / Number of copies: 1 / Formula: LNK
Molecular weightTheoretical: 72.149 Da
Chemical component information

ChemComp-LNK:
PENTANE

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Macromolecule #11: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 11 / Number of copies: 1 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: Ab initio
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 892902
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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