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- PDB-7txt: Structure of human serotonin transporter bound to small molecule ... -

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Basic information

Entry
Database: PDB / ID: 7txt
TitleStructure of human serotonin transporter bound to small molecule '8090 in lipid nanodisc and NaCl
Components
  • 15B8 Fab heavy chain
  • 15B8 Fab light chain
  • Sodium-dependent serotonin transporter
KeywordsTRANSPORT PROTEIN / Neurotransmitter transporter / small molecule / 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 / sperm ejaculation / serotonin:sodium:chloride symporter activity / negative regulation of synaptic transmission, dopaminergic / neurotransmitter transmembrane transporter activity ...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 / sperm ejaculation / serotonin:sodium:chloride symporter activity / negative regulation of synaptic transmission, dopaminergic / neurotransmitter transmembrane transporter activity / enteric nervous system development / serotonin uptake / cellular response to cGMP / negative regulation of organ growth / sodium ion binding / monoamine transmembrane transporter activity / monoamine transport / serotonin binding / vasoconstriction / brain morphogenesis / neurotransmitter transport / antiporter activity / syntaxin-1 binding / nitric-oxide synthase binding / membrane depolarization / social behavior / negative regulation of neuron differentiation / sodium ion transmembrane transport / endomembrane system / monoatomic cation channel activity / positive regulation of cell cycle / cellular response to retinoic acid / response to nutrient / response to toxic substance / memory / platelet aggregation / circadian rhythm / actin filament binding / integrin binding / response to estradiol / presynaptic membrane / postsynaptic membrane / endosome membrane / response to hypoxia / response to xenobiotic stimulus / neuron projection / 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
1-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperazine / Sodium-dependent serotonin transporter
Similarity search - Component
Biological speciesMus musculus (house mouse)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsSingh, I. / Seth, A. / Billesboelle, C.B. / Braz, J. / Rodriguiz, R.M. / Roy, K. / Bekele, B. / Craik, V. / Huang, X.P. / Boytsov, D. ...Singh, I. / Seth, A. / Billesboelle, C.B. / Braz, J. / Rodriguiz, R.M. / Roy, K. / Bekele, B. / Craik, V. / Huang, X.P. / Boytsov, D. / Lak, P. / O'Donnell, H. / Sandtner, W. / Roth, B.L. / Basbaum, A.I. / Wetsel, W.C. / Manglik, A. / Shoichet, B.K. / Rudnick, G.
Funding support United States, 1items
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, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 15, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: 15B8 Fab heavy chain
D: 15B8 Fab light chain
S: Sodium-dependent serotonin transporter
hetero molecules


Theoretical massNumber of molelcules
Total (without water)86,3974
Polymers86,1343
Non-polymers2631
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Antibody 15B8 Fab heavy chain


Mass: 13166.742 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#2: Antibody 15B8 Fab light chain


Mass: 11905.246 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#3: Protein Sodium-dependent serotonin transporter / SERT / 5HT transporter / 5HTT / Solute carrier family 6 member 4


Mass: 61062.129 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: Chemical ChemComp-KWC / 1-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperazine


Mass: 263.334 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H14FN3S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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

Component
IDNameTypeEntity IDParent-IDSource
1Human serotonin transporter in complex with Fab15B8 bound to '8090 in NaClCOMPLEX#1-#30MULTIPLE SOURCES
2Sodium-dependent serotonin transporterCOMPLEX#31RECOMBINANT
3Fab15B8 heavy chainCOMPLEX#11RECOMBINANT
4Fab15B8 light chainCOMPLEX#21RECOMBINANT
Molecular weight
IDEntity assembly-IDExperimental value
11
21NO
31NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
32Homo sapiens (human)9606
43Mus musculus (house mouse)10090
54Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
32Homo sapiens (human)9606
43Homo sapiens (human)9606
54Homo sapiens (human)9606
Buffer solutionpH: 7.5
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
VitrificationCryogen name: ETHANE

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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 FIELDBright-field microscopy / Nominal defocus max: 2100 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARC3.2.0particle selection
2SerialEM3.8image acquisition
4cryoSPARC3.2.0CTF correction
9cryoSPARC3.2.0initial Euler assignment
10cryoSPARC3.2.0final Euler assignment
12cryoSPARC3.2.03D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 187696 / Symmetry type: POINT

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