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Yorodumi- PDB-7txt: Structure of human serotonin transporter bound to small molecule ... -
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-Basic information
Entry | Database: PDB / ID: 7txt | ||||||
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Title | Structure of human serotonin transporter bound to small molecule '8090 in lipid nanodisc and NaCl | ||||||
Components |
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Keywords | TRANSPORT 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 / serotonergic synapse / Serotonin clearance from the synaptic cleft / 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 / serotonergic synapse / Serotonin clearance from the synaptic cleft / positive regulation of serotonin secretion / cocaine binding / negative regulation of synaptic transmission, dopaminergic / sperm ejaculation / serotonin:sodium:chloride symporter activity / cellular response to cGMP / sodium ion binding / enteric nervous system development / negative regulation of organ growth / serotonin uptake / neurotransmitter transmembrane transporter activity / serotonin binding / monoamine transmembrane transporter activity / monoamine transport / conditioned place preference / vasoconstriction / brain morphogenesis / antiporter activity / neurotransmitter transport / syntaxin-1 binding / amino acid transport / nitric-oxide synthase binding / behavioral response to cocaine / membrane depolarization / social behavior / negative regulation of neuron differentiation / sodium ion transmembrane transport / endomembrane system / positive regulation of cell cycle / cellular response to retinoic acid / monoatomic cation channel activity / 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 | ||||||
Biological species | Mus musculus (house mouse) Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å | ||||||
Authors | Singh, 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
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7txt.cif.gz | 275.1 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7txt.ent.gz | 221.9 KB | Display | PDB format |
PDBx/mmJSON format | 7txt.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7txt_validation.pdf.gz | 844.7 KB | Display | wwPDB validaton report |
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Full document | 7txt_full_validation.pdf.gz | 851.1 KB | Display | |
Data in XML | 7txt_validation.xml.gz | 27.7 KB | Display | |
Data in CIF | 7txt_validation.cif.gz | 40.5 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/tx/7txt ftp://data.pdbj.org/pub/pdb/validation_reports/tx/7txt | HTTPS FTP |
-Related structure data
Related structure data | 26160MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Antibody | 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) |
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#2: Antibody | 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 | 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 / |
Has ligand of interest | Y |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
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Molecular weight |
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Source (recombinant) |
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Buffer solution | pH: 7.5 | ||||||||||||||||||||||||||||||
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||||||||
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3 | ||||||||||||||||||||||||||||||
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: TFS KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2100 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 187696 / Symmetry type: POINT |