RCSB PDB - 6M2R: X-ray structure of a functional Drosophila dopamine transporter in L-norepinephrine bound form

 6M2R

X-ray structure of a functional Drosophila dopamine transporter in L-norepinephrine bound form


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.213 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

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This is version 1.3 of the entry. See complete history


Literature

Structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters.

Pidathala, S.Mallela, A.K.Joseph, D.Penmatsa, A.

(2021) Nat Commun 12: 2199-2199

  • DOI: https://doi.org/10.1038/s41467-021-22385-9
  • Primary Citation of Related Structures:  
    6M0F, 6M0Z, 6M2R, 6M38, 6M3Z, 6M47

  • PubMed Abstract: 

    Norepinephrine is a biogenic amine neurotransmitter that has widespread effects on alertness, arousal and pain sensation. Consequently, blockers of norepinephrine uptake have served as vital tools to treat depression and chronic pain. Here, we employ the Drosophila melanogaster dopamine transporter as a surrogate for the norepinephrine transporter and determine X-ray structures of the transporter in its substrate-free and norepinephrine-bound forms. We also report structures of the transporter in complex with inhibitors of chronic pain including duloxetine, milnacipran and a synthetic opioid, tramadol. When compared to dopamine, we observe that norepinephrine binds in a different pose, in the vicinity of subsite C within the primary binding site. Our experiments reveal that this region is the binding site for chronic pain inhibitors and a determinant for norepinephrine-specific reuptake inhibition, thereby providing a paradigm for the design of specific inhibitors for catecholamine neurotransmitter transporters.


  • Organizational Affiliation

    Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Sodium-dependent dopamine transporter536Drosophila melanogasterMutation(s): 3 
Gene Names: DATfmnCG8380
Membrane Entity: Yes 
UniProt
Find proteins for Q7K4Y6 (Drosophila melanogaster)
Explore Q7K4Y6 
Go to UniProtKB:  Q7K4Y6
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ7K4Y6
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Antibody fragment 9D5 Light chainB [auth L]214Mus 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
Antibody fragment 9D5 heavy chainC [auth H]219Mus musculusMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 7 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
Y01
Query on Y01

Download Ideal Coordinates CCD File 
E [auth A]CHOLESTEROL HEMISUCCINATE
C31 H50 O4
WLNARFZDISHUGS-MIXBDBMTSA-N
DMU
Query on DMU

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D [auth A]DECYL-BETA-D-MALTOPYRANOSIDE
C22 H42 O11
WOQQAWHSKSSAGF-WXFJLFHKSA-N
CLR
Query on CLR

Download Ideal Coordinates CCD File 
F [auth A]CHOLESTEROL
C27 H46 O
HVYWMOMLDIMFJA-DPAQBDIFSA-N
LNR (Subject of Investigation/LOI)
Query on LNR

Download Ideal Coordinates CCD File 
G [auth A]L-NOREPINEPHRINE
C8 H11 N O3
SFLSHLFXELFNJZ-QMMMGPOBSA-N
D10
Query on D10

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K [auth A],
L [auth A],
M [auth A]
DECANE
C10 H22
DIOQZVSQGTUSAI-UHFFFAOYSA-N
CL
Query on CL

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H [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
NA
Query on NA

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I [auth A],
J [auth A],
N [auth L],
O [auth L]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.213 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 96.8α = 90
b = 141.27β = 90
c = 167.711γ = 90
Software Package:
Software NamePurpose
Aimlessdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted LNRClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Department of Biotechnology (DBT, India)IndiaIA/1/15/2/502063
Department of Biotechnology (DBT, India)IndiaBT/09/IYBA/2015/13

Revision History  (Full details and data files)

  • Version 1.0: 2021-02-17
    Type: Initial release
  • Version 1.1: 2021-04-28
    Changes: Database references
  • Version 1.2: 2023-11-29
    Changes: Data collection, Database references, Refinement description
  • Version 1.3: 2024-10-09
    Changes: Structure summary