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- EMDB-8943: Cryo-EM Structure of the wild-type human serotonin transporter in... -

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Entry
Database: EMDB / ID: EMD-8943
TitleCryo-EM Structure of the wild-type human serotonin transporter in complex with ibogaine and 15B8 Fab in the inward conformation
Map dataWild-type SERT bound to Fab and in complex with ibogaine in the occluded and inward conformations
Sample
  • Complex: Human serotonin transporter in complex with Fab bound to ibogaine
    • Complex: serotonin transporter
      • Protein or peptide: Sodium-dependent serotonin transporter
    • Complex: 15B8 Fab
      • Protein or peptide: 15B8 antibody heavy chain
      • Protein or peptide: 15B8 antibody light chain
  • Ligand: (5beta)-12-methoxyibogamine
  • Ligand: DODECYL-BETA-D-MALTOSIDE
Keywordsibogaine / human serotonin transporter / Fab / TRANSPORT PROTEIN-IMMUNE SYSTEM 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 / positive regulation of serotonin secretion / serotonergic synapse / negative regulation of synaptic transmission, dopaminergic / cocaine binding / serotonin:sodium:chloride symporter activity / cellular response to cGMP / enteric nervous system development ...negative regulation of cerebellar granule cell precursor proliferation / regulation of thalamus size / Serotonin clearance from the synaptic cleft / positive regulation of serotonin secretion / serotonergic synapse / negative regulation of synaptic transmission, dopaminergic / cocaine binding / serotonin:sodium:chloride symporter activity / cellular response to cGMP / enteric nervous system development / negative regulation of organ growth / sodium ion binding / neurotransmitter transmembrane transporter activity / serotonin uptake / vasoconstriction / monoamine transmembrane transporter activity / monoamine transport / serotonin binding / brain morphogenesis / syntaxin-1 binding / antiporter activity / negative regulation of neuron differentiation / male mating behavior / neurotransmitter transport / nitric-oxide synthase binding / amino acid transport / conditioned place preference / membrane depolarization / monoatomic cation channel activity / behavioral response to cocaine / positive regulation of cell cycle / cellular response to retinoic acid / response to nutrient / endomembrane system / sodium ion transmembrane transport / circadian rhythm / response to toxic substance / platelet aggregation / memory / integrin binding / actin filament binding / response to estradiol / presynaptic membrane / postsynaptic membrane / response to hypoxia / neuron projection / endosome membrane / membrane raft / response to xenobiotic stimulus / 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: 3.6 Å
AuthorsYang D / Coleman JA
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)5R37MH070039 United States
CitationJournal: Nature / Year: 2019
Title: Serotonin transporter-ibogaine complexes illuminate mechanisms of inhibition and transport.
Authors: Jonathan A Coleman / Dongxue Yang / Zhiyu Zhao / Po-Chao Wen / Craig Yoshioka / Emad Tajkhorshid / Eric Gouaux /
Abstract: The serotonin transporter (SERT) regulates neurotransmitter homeostasis through the sodium- and chloride-dependent recycling of serotonin into presynaptic neurons. Major depression and anxiety ...The serotonin transporter (SERT) regulates neurotransmitter homeostasis through the sodium- and chloride-dependent recycling of serotonin into presynaptic neurons. Major depression and anxiety disorders are treated using selective serotonin reuptake inhibitors-small molecules that competitively block substrate binding and thereby prolong neurotransmitter action. The dopamine and noradrenaline transporters, together with SERT, are members of the neurotransmitter sodium symporter (NSS) family. The transport activities of NSSs can be inhibited or modulated by cocaine and amphetamines, and genetic variants of NSSs are associated with several neuropsychiatric disorders including attention deficit hyperactivity disorder, autism and bipolar disorder. Studies of bacterial NSS homologues-including LeuT-have shown how their transmembrane helices (TMs) undergo conformational changes during the transport cycle, exposing a central binding site to either side of the membrane. However, the conformational changes associated with transport in NSSs remain unknown. To elucidate structure-based mechanisms for transport in SERT we investigated its complexes with ibogaine, a hallucinogenic natural product with psychoactive and anti-addictive properties. Notably, ibogaine is a non-competitive inhibitor of transport but displays competitive binding towards selective serotonin reuptake inhibitors. Here we report cryo-electron microscopy structures of SERT-ibogaine complexes captured in outward-open, occluded and inward-open conformations. Ibogaine binds to the central binding site, and closure of the extracellular gate largely involves movements of TMs 1b and 6a. Opening of the intracellular gate involves a hinge-like movement of TM1a and the partial unwinding of TM5, which together create a permeation pathway that enables substrate and ion diffusion to the cytoplasm. These structures define the structural rearrangements that occur from the outward-open to inward-open conformations, and provide insight into the mechanism of neurotransmitter transport and ibogaine inhibition.
History
DepositionJul 5, 2018-
Header (metadata) releaseMar 13, 2019-
Map releaseApr 24, 2019-
UpdateMay 14, 2025-
Current statusMay 14, 2025Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 6.5
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 6.5
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6dzz
  • Surface level: 6.5
  • Imaged by UCSF Chimera
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Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_8943.png

Downloads & links

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Map

FileDownload / File: emd_8943.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationWild-type SERT bound to Fab and in complex with ibogaine in the occluded and inward conformations
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 380 pix.
= 312.74 Å		0.82 Å/pix.
x 380 pix.
= 312.74 Å		0.82 Å/pix.
x 380 pix.
= 312.74 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.823 Å
Density

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Histogram (log scale)
Contour LevelBy AUTHOR: 5.4 / Movie #1: 6.5
Minimum - Maximum-16.325887999999999 - 31.559052999999999
Average (Standard dev.)0.03612217 (±1.3513336)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions380380380
Spacing380380380
CellA=B=C: 312.74 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8230.8230.823
M x/y/z380380380
origin x/y/z0.0000.0000.000
length x/y/z312.740312.740312.740
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS380380380
D min/max/mean-16.32631.5590.036

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Supplemental data

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Mask #1

Fileemd_8943_msk_1.map
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Mask #2

Fileemd_8943_msk_2.map
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Additional map: Unsharpened map, data set 2

Fileemd_8943_additional_1.map
AnnotationUnsharpened map, data set 2
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Additional map: Unsharpened map, data set 1

Fileemd_8943_additional_2.map
AnnotationUnsharpened map, data set 1
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Additional map: half map 2, data set 2

Fileemd_8943_additional_3.map
Annotationhalf map 2, data set 2
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Additional map: half map 1, data set 2

Fileemd_8943_additional_4.map
Annotationhalf map 1, data set 2
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Additional map: Inward class, data set 1

Fileemd_8943_additional_5.map
AnnotationInward class, data set 1
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Additional map: Occluded class, data set 1

Fileemd_8943_additional_6.map
AnnotationOccluded class, data set 1
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Additional map: Unsharpened, aligned and averaged map from data set 1 and 2

Fileemd_8943_additional_7.map
AnnotationUnsharpened, aligned and averaged map from data set 1 and 2
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Additional map: inward class, low resolution

Fileemd_8943_additional_8.map
Annotationinward class, low resolution
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Additional map: inward class, unsharpened map

Fileemd_8943_additional_9.map
Annotationinward class, unsharpened map
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Half map: Half map 2, data set 1

Fileemd_8943_half_map_1.map
AnnotationHalf map 2, data set 1
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Half map: Half map 1, data set 1

Fileemd_8943_half_map_2.map
AnnotationHalf map 1, data set 1
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Sample components

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Entire : Human serotonin transporter in complex with Fab bound to ibogaine

EntireName: Human serotonin transporter in complex with Fab bound to ibogaine
Components
  • Complex: Human serotonin transporter in complex with Fab bound to ibogaine
    • Complex: serotonin transporter
      • Protein or peptide: Sodium-dependent serotonin transporter
    • Complex: 15B8 Fab
      • Protein or peptide: 15B8 antibody heavy chain
      • Protein or peptide: 15B8 antibody light chain
  • Ligand: (5beta)-12-methoxyibogamine
  • Ligand: DODECYL-BETA-D-MALTOSIDE

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Supramolecule #1: Human serotonin transporter in complex with Fab bound to ibogaine

SupramoleculeName: Human serotonin transporter in complex with Fab bound to ibogaine
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3

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Supramolecule #2: serotonin transporter

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

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Supramolecule #3: 15B8 Fab

SupramoleculeName: 15B8 Fab / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Mus musculus (house mouse)

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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: 61.005074 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ERETWGKKVD FLLSVIGYAV DLGNVWRFPY ICYQNGGGAF LLPYTIMAIF GGIPLFYMEL ALGQYHRNGC ISIWRKICPI FKGIGYAIC IIAFYIASYY NTIMAWALYY LISSFTDQLP WTSCKNSWNT GNCTNYFSED NITWTLHSTS PAEEFYTRHV L QIHRSKGL ...String:
ERETWGKKVD FLLSVIGYAV DLGNVWRFPY ICYQNGGGAF LLPYTIMAIF GGIPLFYMEL ALGQYHRNGC ISIWRKICPI FKGIGYAIC IIAFYIASYY NTIMAWALYY LISSFTDQLP WTSCKNSWNT GNCTNYFSED NITWTLHSTS PAEEFYTRHV L QIHRSKGL QDLGGISWQL ALCIMLIFTV IYFSIWKGVK TSGKVVWVTA TFPYIILSVL LVRGATLPGA WRGVLFYLKP NW QKLLETG VWIDAAAQIF FSLGPGFGVL LAFASYNKFN NNCYQDALVT SVVNCMTSFV SGFVIFTVLG YMAEMRNEDV SEV AKDAGP SLLFITYAEA IANMPASTFF AIIFFLMLIT LGLDSTFAGL EGVITAVLDE FPHVWAKRRE RFVLAVVITC FFGS LVTLT FGGAYVVKLL EEYATGPAVL TVALIEAVAV SWFYGITQFC RDVKEMLGFS PGWFWRICWV AISPLFLLFI ICSFL MSPP QLRLFQYNYP YWSIILGYCI GTSSFICIPT YIAYRLIITP GTFKERIIKS ITPETP

UniProtKB: Sodium-dependent serotonin transporter

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Macromolecule #2: 15B8 antibody heavy chain

MacromoleculeName: 15B8 antibody 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
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString:
QVQLQQSGPE LVKLGASVRI SCKASGYRFS YSWMNWVKQR PGKGLEWIGR IYPGDGDTKY SGKFKGKATL TADKSSSTVY MQLSSLTSE DSAVYFCARS AYGSEGFAMD YWGQGTSVT

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Macromolecule #3: 15B8 antibody light chain

MacromoleculeName: 15B8 antibody 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
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString:
DIVLTQSPAS LAVSLGQRAT ISCRASESVD NYGISFLNWF QQKPGQPPKL LIYAASNQGS GVPARFSGSG SGTYFSLNIH PMEEDDTAV YFCQQTKGVS WTFGGGTKVE I

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Macromolecule #5: (5beta)-12-methoxyibogamine

MacromoleculeName: (5beta)-12-methoxyibogamine / type: ligand / ID: 5 / Number of copies: 1 / Formula: HJM
Molecular weightTheoretical: 310.433 Da
Chemical component information

ChemComp-HJM:
(5beta)-12-methoxyibogamine

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Macromolecule #6: DODECYL-BETA-D-MALTOSIDE

MacromoleculeName: DODECYL-BETA-D-MALTOSIDE / type: ligand / ID: 6 / Number of copies: 1 / Formula: LMT
Molecular weightTheoretical: 510.615 Da
Chemical component information

ChemComp-LMT:
DODECYL-BETA-D-MALTOSIDE / detergent*YM

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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
GridDetails: unspecified
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 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

CTF correctionType: PHASE FLIPPING ONLY
Startup modelType of model: OTHER / Details: Ab initio
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 368656
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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