4XNX

X-ray structure of Drosophila dopamine transporter in complex with reboxetine

PDB DOI: https://doi.org/10.2210/pdb4XNX/pdb

Classification: transport protein/inhibitor
Organism(s): Drosophila melanogaster, Mus musculus
Expression System: Homo sapiens, Mus musculus
Mutation(s): Yes
Membrane Protein: Yes PDBTMMemProtMDmpstruc

Deposited: 2015-01-16 Released: 2015-05-13
Deposition Author(s): Aravind, P., Wang, K., Gouaux, E.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 3.00 Å
R-Value Free:
0.258 (Depositor), 0.260 (DCC)
R-Value Work:
0.217 (Depositor), 0.220 (DCC)
R-Value Observed:
0.219 (Depositor)

Starting Model: experimental
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Ligand Structure Quality Assessment

This is version 2.2 of the entry. See complete history.

Literature

X-ray structures of Drosophila dopamine transporter in complex with nisoxetine and reboxetine.

Penmatsa, A., Wang, K.H., Gouaux, E.

(2015) Nat Struct Mol Biol 22: 506-508

PubMed: 25961798 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1038/nsmb.3029
Primary Citation of Related Structures:
4XNU, 4XNX

PubMed Abstract:
Most antidepressants elicit their therapeutic benefits through selective blockade of Na(+)/Cl(-)-coupled neurotransmitter transporters. Here we report X-ray structures of the Drosophila melanogaster dopamine transporter in complexes with the polycyclic antidepressants nisoxetine or reboxetine. The inhibitors stabilize the transporter in an outward-open conformation by occupying the substrate-binding site. These structures explain how interactions between the binding pocket and substituents on the aromatic rings of antidepressants modulate drug-transporter selectivity.

Organizational Affiliation

Vollum Institute, Oregon Health & Science University, Portland OR.

Macromolecule Content

Total Structure Weight: 110.89 kDa
Atom Count: 7,514
Modelled Residue Count: 966
Deposited Residue Count: 990
Unique protein chains: 3

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Transporter	A	536	Drosophila melanogaster	Mutation(s): 2 Gene Names: DAT, Dmel_CG8380 Membrane Entity: Yes
UniProt
Find proteins for Q7K4Y6 (Drosophila melanogaster) Explore Q7K4Y6 Go to UniProtKB: Q7K4Y6
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q7K4Y6
Sequence Annotations Expand
Reference Sequence LOADING

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(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
antibody fragment light chain	B [auth L]	214	Mus musculus	Mutation(s): 0
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations Expand
Reference Sequence LOADING

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(by identity cutoff) | 3D Structure

Entity ID: 3
Molecule	Chains	Sequence Length	Organism	Details	Image
Antibody fragment heavy chain	C [auth H]	240	Mus musculus	Mutation(s): 0
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations Expand
Reference Sequence LOADING

Oligosaccharides

Help

Entity ID: 4
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
alpha-D-glucopyranose-(1-4)-beta-D-glucopyranose	D [auth B]	2		N/A	Interactions Focus chain D [auth B] Interactions & Density Focus chain D [auth B]
Glycosylation Resources
GlyTouCan: G66120GK GlyCosmos: G66120GK

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
CLR Query on CLR Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A]	E [auth A], F [auth A]	CHOLESTEROL C₂₇ H₄₆ O HVYWMOMLDIMFJA-DPAQBDIFSA-N		Interactions Focus chain E [auth A] Focus chain F [auth A] Interactions & Density Focus chain E [auth A] Focus chain F [auth A]
41X Query on 41X Download Ideal Coordinates CCD File SDF format, chain J [auth A] MOL2 format, chain J [auth A] mmCIF format, chain J [auth A]	J [auth A]	(2R)-2-[(R)-(2-ethoxyphenoxy)(phenyl)methyl]morpholine C₁₉ H₂₃ N O₃ CBQGYUDMJHNJBX-RTBURBONSA-N		Interactions Focus chain J [auth A] Interactions & Density Focus chain J [auth A]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain I [auth A] MOL2 format, chain I [auth A] mmCIF format, chain I [auth A]	I [auth A]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain I [auth A] Interactions & Density Focus chain I [auth A]
NA Query on NA Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain H [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A]	G [auth A], H [auth A]	SODIUM ION Na FKNQFGJONOIPTF-UHFFFAOYSA-N		Interactions Focus chain G [auth A] Focus chain H [auth A] Interactions & Density Focus chain G [auth A] Focus chain H [auth A]

Biologically Interesting Molecules (External Reference) 1 Unique

Entity ID: 4
ID	Chains	Name	Type/Class	2D Diagram	3D Interactions
PRD_900018 Query on PRD_900018	D [auth B]	beta-maltose	Oligosaccharide / Nutrient		Interactions Focus chain D [auth B] Interactions & Density Focus chain D [auth B]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 3.00 Å
R-Value Free: 0.258 (Depositor), 0.260 (DCC)
R-Value Work: 0.217 (Depositor), 0.220 (DCC)
R-Value Observed: 0.219 (Depositor)

Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 97.673	α = 90
b = 141.036	β = 90
c = 167.247	γ = 90

Software Package:

Software Name	Purpose
PHENIX	refinement
HKL-2000	data reduction
PDB_EXTRACT	data extraction
SCALEPACK	data scaling
PHASER	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2015-05-13

Deposition Author(s):

Aravind, P.

Wang, K.

Gouaux, E.

Revision History (Full details and data files)

Version 1.0: 2015-05-13
Type: Initial release
Version 1.1: 2015-05-27
Changes: Database references
Version 1.2: 2015-06-10
Changes: Database references
Version 1.3: 2017-05-31
Changes: Other
Version 2.0: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Atomic model, Data collection, Derived calculations, Non-polymer description, Structure summary
Version 2.1: 2023-09-27
Changes: Data collection, Database references, Refinement description, Structure summary
Version 2.2: 2024-11-13
Changes: Structure summary