5I73

X-ray structure of the ts3 human serotonin transporter complexed with s-citalopram at the central and allosteric sites


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.24 Å
  • R-Value Free: 0.275 
  • R-Value Work: 0.233 
  • R-Value Observed: 0.235 

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Ligand Structure Quality Assessment 


This is version 2.0 of the entry. See complete history


Literature

X-ray structures and mechanism of the human serotonin transporter.

Coleman, J.A.Green, E.M.Gouaux, E.

(2016) Nature 532: 334-339

  • DOI: https://doi.org/10.1038/nature17629
  • Primary Citation of Related Structures:  
    5I66, 5I6X, 5I6Z, 5I71, 5I73, 5I74, 5I75

  • PubMed Abstract: 

    The serotonin transporter (SERT) terminates serotonergic signalling through the sodium- and chloride-dependent reuptake of neurotransmitter into presynaptic neurons. SERT is a target for antidepressant and psychostimulant drugs, which block reuptake and prolong neurotransmitter signalling. Here we report X-ray crystallographic structures of human SERT at 3.15 Å resolution bound to the antidepressants (S)-citalopram or paroxetine. Antidepressants lock SERT in an outward-open conformation by lodging in the central binding site, located between transmembrane helices 1, 3, 6, 8 and 10, directly blocking serotonin binding. We further identify the location of an allosteric site in the complex as residing at the periphery of the extracellular vestibule, interposed between extracellular loops 4 and 6 and transmembrane helices 1, 6, 10 and 11. Occupancy of the allosteric site sterically hinders ligand unbinding from the central site, providing an explanation for the action of (S)-citalopram as an allosteric ligand. These structures define the mechanism of antidepressant action in SERT, and provide blueprints for future drug design.


  • Organizational Affiliation

    Vollum Institute, Oregon Health &Science University, Portland, Oregon 97239, USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Sodium-dependent serotonin transporter549Homo sapiensMutation(s): 4 
Gene Names: SLC6A4HTTSERT
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P31645 (Homo sapiens)
Explore P31645 
Go to UniProtKB:  P31645
PHAROS:  P31645
GTEx:  ENSG00000108576 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP31645
Glycosylation
Glycosylation Sites: 2Go to GlyGen: P31645-1
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
8B6 antibody, heavy chain221Mus musculusMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
8B6 antibody, light chain214Mus musculusMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
CLR
Query on CLR

Download Ideal Coordinates CCD File 
F [auth A]CHOLESTEROL
C27 H46 O
HVYWMOMLDIMFJA-DPAQBDIFSA-N
68P
Query on 68P

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D [auth A],
H [auth A]
(1S)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile
C20 H21 F N2 O
WSEQXVZVJXJVFP-FQEVSTJZSA-N
NAG
Query on NAG

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E [auth A],
I [auth A]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
C14
Query on C14

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G [auth A]TETRADECANE
C14 H30
BGHCVCJVXZWKCC-UHFFFAOYSA-N
ACA
Query on ACA

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L [auth A]6-AMINOHEXANOIC ACID
C6 H13 N O2
SLXKOJJOQWFEFD-UHFFFAOYSA-N
NA
Query on NA

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J [auth A],
K [auth A]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
68P BindingDB:  5I73 Ki: min: 0.65, max: 32.8 (nM) from 28 assay(s)
Kd: 2.6 (nM) from 1 assay(s)
IC50: min: 1.8, max: 4600 (nM) from 15 assay(s)
EC50: min: 5100, max: 8700 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.24 Å
  • R-Value Free: 0.275 
  • R-Value Work: 0.233 
  • R-Value Observed: 0.235 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 129.85α = 90
b = 163.21β = 90
c = 140.47γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-04-13
    Type: Initial release
  • Version 1.1: 2016-04-20
    Changes: Database references
  • Version 1.2: 2016-05-04
    Changes: Database references
  • Version 1.3: 2020-03-04
    Changes: Data collection, Database references, Derived calculations
  • Version 1.4: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Derived calculations, Structure summary
  • Version 2.0: 2023-11-15
    Changes: Atomic model, Data collection, Database references, Structure summary