6ESY

Human butyrylcholinesterase in complex with thioflavine T


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.209 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Comparison of the Binding of Reversible Inhibitors to Human Butyrylcholinesterase and Acetylcholinesterase: A Crystallographic, Kinetic and Calorimetric Study.

Rosenberry, T.L.Brazzolotto, X.Macdonald, I.R.Wandhammer, M.Trovaslet-Leroy, M.Darvesh, S.Nachon, F.

(2017) Molecules 22

  • DOI: https://doi.org/10.3390/molecules22122098
  • Primary Citation of Related Structures:  
    6EP4, 6EQP, 6EQQ, 6ESJ, 6ESY

  • PubMed Abstract: 

    Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) hydrolyze the neurotransmitter acetylcholine and, thereby, function as coregulators of cholinergic neurotransmission. Although closely related, these enzymes display very different substrate specificities that only partially overlap. This disparity is largely due to differences in the number of aromatic residues lining the active site gorge, which leads to large differences in the shape of the gorge and potentially to distinct interactions with an individual ligand. Considerable structural information is available for the binding of a wide diversity of ligands to AChE. In contrast, structural data on the binding of reversible ligands to BChE are lacking. In a recent effort, an inhibitor competition approach was used to probe the overlap of ligand binding sites in BChE. Here, we extend this study by solving the crystal structures of human BChE in complex with five reversible ligands, namely, decamethonium, thioflavin T, propidium, huprine, and ethopropazine. We compare these structures to equivalent AChE complexes when available in the protein data bank and supplement this comparison with kinetic data and observations from isothermal titration calorimetry. This new information now allows us to define the binding mode of various ligand families and will be of importance in designing specific reversible ligands of BChE that behave as inhibitors or reactivators.


  • Organizational Affiliation

    Departments of Neuroscience and Pharmacology, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA. rosenberry@mayo.edu.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cholinesterase
A, B
529Homo sapiensMutation(s): 0 
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
Sequence Annotations
Expand
  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
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
C, H
3N-Glycosylation
Glycosylation Resources
GlyTouCan:  G21290RB
GlyCosmos:  G21290RB
GlyGen:  G21290RB
Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
D, E, G
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Entity ID: 4
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose
F
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G86851RC
GlyCosmos:  G86851RC
GlyGen:  G86851RC
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
TFX (Subject of Investigation/LOI)
Query on TFX

Download Ideal Coordinates CCD File 
K [auth A],
L [auth A],
S [auth B],
T [auth B]
2-[4-(dimethylamino)phenyl]-3,6-dimethyl-1,3-benzothiazol-3-ium
C17 H19 N2 S
FXEKRIDRIFBJOR-UHFFFAOYSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
I [auth A]
J [auth A]
N [auth B]
O [auth B]
P [auth B]
I [auth A],
J [auth A],
N [auth B],
O [auth B],
P [auth B],
Q [auth B],
R [auth B]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
M [auth A],
U [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
TFX BindingDB:  6ESY Ki: 3620 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.209 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.27α = 90
b = 79.25β = 90
c = 228.92γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
XSCALEdata scaling
PHASERphasing
PHENIXrefinement
Cootmodel building

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
French Ministry of Armed ForcesFrance--

Revision History  (Full details and data files)

  • Version 1.0: 2017-12-13
    Type: Initial release
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Derived calculations, Structure summary
  • Version 2.1: 2024-01-17
    Changes: Advisory, Data collection, Database references, Derived calculations, Refinement description, Structure summary