6ZWI

Human butyrylcholinesterase in complex with ((6-((2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienamido)hexyl)triphenylphosphonium bromide)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.189 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases.

Chavarria, D.Da Silva, O.Benfeito, S.Barreiro, S.Garrido, J.Cagide, F.Soares, P.Remiao, F.Brazzolotto, X.Nachon, F.Oliveira, P.J.Dias, J.Borges, F.

(2021) Antioxidants (Basel) 10

  • DOI: https://doi.org/10.3390/antiox10020329
  • Primary Citation of Related Structures:  
    6ZWE, 6ZWI

  • PubMed Abstract: 

    Neurotransmitter depletion and mitochondrial dysfunction are among the multiple pathological events that lead to neurodegeneration. Following our previous studies related with the development of multitarget mitochondriotropic antioxidants, this study aims to evaluate whether the π-system extension on the chemical scaffolds of AntiOXCIN2 and AntiOXCIN3 affects their bioactivity and safety profiles. After the synthesis of four triphenylphosphonium (TPP + ) conjugates (compounds 2 - 5 ), we evaluated their antioxidant properties and their effect on neurotransmitter-metabolizing enzymes. All compounds were potent equine butyrylcholinesterase ( eq BChE) and moderate electric eel acetylcholinesterase ( ee AChE) inhibitors, with catechols 4 and 5 presenting lower IC 50 values than AntiOXCIN2 and AntiOXCIN3, respectively. However, differences in the inhibition potency and selectivity of compounds 2 - 5 towards non-human and human cholinesterases (ChEs) were observed. Co-crystallization studies with compounds 2 - 5 in complex with human ChEs ( h ChEs) showed that these compounds exhibit different binging modes to h AChE and h BChE. Unlike AntiOXCINs, compounds 2 - 5 displayed moderate human monoamine oxidase ( h MAO) inhibitory activity. Moreover, compounds 4 and 5 presented higher ORAC-FL indexes and lower oxidation potential values than the corresponding AntiOXCINs. Catechols 4 and 5 exhibited broader safety windows in differentiated neuroblastoma cells than benzodioxole derivatives 2 and 3. Compound 4 is highlighted as a safe mitochondria-targeted antioxidant with dual ChE/MAO inhibitory activity. Overall, this work is a contribution for the development of dual therapeutic agents addressing both mitochondrial oxidative stress and neurotransmitter depletion.


  • Organizational Affiliation

    CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cholinesterase529Homo sapiensMutation(s): 4 
Gene Names: BCHECHE1
EC: 3.1.1.8
UniProt & NIH Common Fund Data Resources
Find proteins for P06276 (Homo sapiens)
Explore P06276 
Go to UniProtKB:  P06276
PHAROS:  P06276
GTEx:  ENSG00000114200 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP06276
Glycosylation
Glycosylation Sites: 6Go to GlyGen: P06276-1
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose
B
5N-Glycosylation
Glycosylation Resources
GlyTouCan:  G26032DN
GlyCosmos:  G26032DN
GlyGen:  G26032DN
Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
N-acetyl-alpha-neuraminic acid-(2-3)-beta-D-galactopyranose
C
2N/A
Glycosylation Resources
GlyTouCan:  G30207PZ
GlyCosmos:  G30207PZ
GlyGen:  G30207PZ
Entity ID: 4
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose
D
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G86851RC
GlyCosmos:  G86851RC
GlyGen:  G86851RC
Entity ID: 5
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose
E, F
3N-Glycosylation
Glycosylation Resources
GlyTouCan:  G21290RB
GlyCosmos:  G21290RB
GlyGen:  G21290RB
Small Molecules
Ligands 7 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
QRH (Subject of Investigation/LOI)
Query on QRH

Download Ideal Coordinates CCD File 
J [auth A](2~{E},4~{E})-5-(1,3-benzodioxol-5-yl)-~{N}-[6-(triphenyl-$l^{5}-phosphanyl)hexyl]penta-2,4-dienamide
C36 H38 N O3 P
XYBUESNIYRZZQB-XSDFDVSCSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
G [auth A],
H [auth A]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
LEA
Query on LEA

Download Ideal Coordinates CCD File 
K [auth A]PENTANOIC ACID
C5 H10 O2
NQPDZGIKBAWPEJ-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
P [auth A],
Q [auth A],
R [auth A],
S [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
I [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
BR
Query on BR

Download Ideal Coordinates CCD File 
T [auth A],
U [auth A]
BROMIDE ION
Br
CPELXLSAUQHCOX-UHFFFAOYSA-M
CL
Query on CL

Download Ideal Coordinates CCD File 
L [auth A],
M [auth A],
N [auth A],
O [auth A]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.189 
  • Space Group: I 4 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 154.3α = 90
b = 154.3β = 90
c = 127.7γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2021-06-09
    Type: Initial release
  • Version 1.1: 2024-01-31
    Changes: Data collection, Database references, Refinement description