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- PDB-7li9: 5-HT bound serotonin transporter reconstituted in lipid nanodisc ... -

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Basic information

Entry
Database: PDB / ID: 7li9
Title5-HT bound serotonin transporter reconstituted in lipid nanodisc in KCl
Components
  • (variable domain of 15B8 antibody Fab ...) x 2
  • Sodium-dependent serotonin transporter
KeywordsMEMBRANE PROTEIN / serotonin / transport / KCl / inward
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 / cocaine binding / sperm ejaculation / negative regulation of synaptic transmission, dopaminergic / 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 / positive regulation of serotonin secretion / serotonergic synapse / cocaine binding / sperm ejaculation / negative regulation of synaptic transmission, dopaminergic / serotonin:sodium:chloride symporter activity / cellular response to cGMP / enteric nervous system development / sodium ion binding / negative regulation of organ growth / neurotransmitter transmembrane transporter activity / serotonin uptake / monoamine transmembrane transporter activity / monoamine transport / serotonin binding / conditioned place preference / vasoconstriction / brain morphogenesis / syntaxin-1 binding / antiporter activity / neurotransmitter transport / nitric-oxide synthase binding / amino acid transport / behavioral response to cocaine / membrane depolarization / negative regulation of neuron differentiation / monoatomic cation channel activity / cellular response to retinoic acid / positive regulation of cell cycle / response to nutrient / sodium ion transmembrane transport / endomembrane system / memory / platelet aggregation / 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 / 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. / Immunoglobulins / Immunoglobulin-like ...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. / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
DECANE / DODECANE / HEPTANE / PENTANE / SEROTONIN / Sodium-dependent serotonin transporter
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsYang, D. / Gouaux, E.
Funding support United States, 2items
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, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 15, 2021Provider: repository / Type: Initial release
Revision 1.1Dec 25, 2024Group: Advisory / Data collection ...Advisory / Data collection / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature / pdbx_validate_close_contact / struct_conn
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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Assembly

Deposited unit
A: Sodium-dependent serotonin transporter
B: variable domain of 15B8 antibody Fab heavy chain
C: variable domain of 15B8 antibody Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)87,48515
Polymers85,6333
Non-polymers1,85212
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Antibody , 2 types, 2 molecules BC

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


Mass: 12980.533 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)
#3: Antibody variable domain of 15B8 antibody Fab light chain


Mass: 11776.065 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)

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Protein / Sugars , 2 types, 2 molecules A

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


Mass: 60875.957 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC6A4, HTT, SERT / Production host: Homo sapiens (human) / References: UniProt: P31645
#4: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE

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Non-polymers , 6 types, 11 molecules

#5: Chemical ChemComp-D12 / DODECANE


Mass: 170.335 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H26
#6: Chemical ChemComp-HP6 / HEPTANE


Mass: 100.202 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H16
#7: Chemical ChemComp-D10 / DECANE


Mass: 142.282 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H22
#8: Chemical ChemComp-LNK / PENTANE


Mass: 72.149 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H12
#9: Chemical ChemComp-SRO / SEROTONIN / 3-(2-AMINOETHYL)-1H-INDOL-5-OL


Mass: 176.215 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H12N2O / Comment: neurotransmitter*YM
#10: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl

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Details

Has ligand of interestN
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: human serotonin transporter in complex with 15B8 Fab in KCl in presence of serotonin
Type: COMPLEX / Entity ID: #1-#3 / Source: MULTIPLE SOURCES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Homo sapiens (human)9606
21Mus musculus (house mouse)10090
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 57 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.17_3644: / Classification: refinement
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 299808 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0026347
ELECTRON MICROSCOPYf_angle_d0.4198609
ELECTRON MICROSCOPYf_dihedral_angle_d11.869896
ELECTRON MICROSCOPYf_chiral_restr0.037942
ELECTRON MICROSCOPYf_plane_restr0.0031049

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