2Y1K

STRUCTURE OF HUMAN BUTYRYLCHOLINESTERASE INHIBITED BY CBDP (12H SOAK): PHOSPHOSERINE ADDUCT


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.185 

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Ligand Structure Quality Assessment 


This is version 4.1 of the entry. See complete history


Literature

Reaction of Cresyl Saligenin Phosphate, the Organophosphorus Agent Implicated in Aerotoxic Syndrome, with Human Cholinesterases: Mechanistic Studies Employing Kinetics, Mass Spectrometry, and X-Ray Structure Analysis.

Carletti, E.Schopfer, L.M.Colletier, J.P.Froment, M.T.Nachon, F.Weik, M.Lockridge, O.Masson, P.

(2011) Chem Res Toxicol 24: 797

  • DOI: https://doi.org/10.1021/tx100447k
  • Primary Citation of Related Structures:  
    2Y1K

  • PubMed Abstract: 

    Aerotoxic syndrome is assumed to be caused by exposure to tricresyl phosphate (TCP), an antiwear additive in jet engine lubricants and hydraulic fluid. CBDP (2-(ortho-cresyl)-4H-1,2,3-benzodioxaphosphoran-2-one) is the toxic metabolite of triortho-cresylphosphate, a component of TCP. Human butyrylcholinesterase (BChE; EC 3.1.1.8) and human acetylcholinesterase (AChE; EC 3.1.1.7) are irreversibly inhibited by CBDP. The bimolecular rate constants of inhibition (k(i)), determined under pseudo-first-order conditions, displayed a biphasic time course of inhibition with k(i) of 1.6 × 10(8) M(-1) min(-1) and 2.7 × 10(7) M(-1) min(-1) for E and E' forms of BChE. The inhibition constants for AChE were 1 to 2 orders of magnitude slower than those for BChE. CBDP-phosphorylated cholinesterases are nonreactivatable due to ultra fast aging. Mass spectrometry analysis showed an initial BChE adduct with an added mass of 170 Da from cresylphosphate, followed by dealkylation to a structure with an added mass of 80 Da. Mass spectrometry in (18)O-water showed that (18)O was incorporated only during the final aging step to form phospho-serine as the final aged BChE adduct. The crystal structure of CBDP-inhibited BChE confirmed that the phosphate adduct is the ultimate aging product. CBDP is the first organophosphorus agent that leads to a fully dealkylated phospho-serine BChE adduct.


  • Organizational Affiliation

    Laboratoire de Biophysique Moléculaire, Institut de Biologie Structurale, 41 Rue Jules Horowitz, 38027 Grenoble, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CHOLINESTERASE529Homo sapiensMutation(s): 3 
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
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose
B
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G86851RC
GlyCosmos:  G86851RC
GlyGen:  G86851RC
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAG
Query on NAG

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

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M [auth A],
S [auth A]
alpha-L-fucopyranose
C6 H12 O5
SHZGCJCMOBCMKK-SXUWKVJYSA-N
SO4
Query on SO4

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C [auth A],
G [auth A],
H [auth A],
J [auth A],
K [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

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F [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
CL
Query on CL

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

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D [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
SEP
Query on SEP
A
L-PEPTIDE LINKINGC3 H8 N O6 PSER
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.185 
  • Space Group: I 4 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 153.77α = 90
b = 153.77β = 90
c = 127.6γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-06-29
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 2.0: 2017-07-12
    Changes: Advisory, Atomic model, Derived calculations
  • Version 3.0: 2017-11-15
    Changes: Advisory, Atomic model, Derived calculations, Non-polymer description, Structure summary
  • Version 4.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Derived calculations, Other, Structure summary
  • Version 4.1: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary