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PDBsum entry 4bc0

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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
4bc0
Jmol
Contents
Protein chains
542 a.a.
Ligands
4OJ ×4
NAG ×7
SO4 ×13
Metals
_CL ×8
Waters ×411
PDB id:
4bc0
Name: Hydrolase
Title: Structure of mouse acetylcholinesterase inhibited by cbdp ( 12-h soak): cresyl-phosphoserine adduct
Structure: Acetylcholinesterase. Chain: a, b, c, d. Engineered: yes. Other_details: cresyl-phosphate adduct on s203
Source: Mus musculus. House mouse. Organism_taxid: 10090. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: cho-k1.
Resolution:
3.35Å     R-factor:   0.163     R-free:   0.207
Authors: E.Carletti,J.-P.Colletier,L.M.Schopfer,G.Santoni,P.Masson, O.Lockridge,F.Nachon,M.Weik
Key ref: E.Carletti et al. (2013). Inhibition pathways of the potent organophosphate CBDP with cholinesterases revealed by X-ray crystallographic snapshots and mass spectrometry. Chem Res Toxicol, 26, 280-289. PubMed id: 23339663 DOI: 10.1021/tx3004505
Date:
30-Sep-12     Release date:   06-Feb-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P21836  (ACES_MOUSE) -  Acetylcholinesterase
Seq:
Struc:
 
Seq:
Struc:
614 a.a.
542 a.a.
Key:    PfamA domain  Secondary structure

 Enzyme reactions 
   Enzyme class: E.C.3.1.1.7  - Acetylcholinesterase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Acetylcholine + H2O = choline + acetate
Acetylcholine
Bound ligand (Het Group name = NAG)
matches with 41.18% similarity
+ H(2)O
= choline
+ acetate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   17 terms 
  Biological process     synapse assembly   13 terms 
  Biochemical function     carboxylic ester hydrolase activity     9 terms  

 

 
    reference    
 
 
DOI no: 10.1021/tx3004505 Chem Res Toxicol 26:280-289 (2013)
PubMed id: 23339663  
 
 
Inhibition pathways of the potent organophosphate CBDP with cholinesterases revealed by X-ray crystallographic snapshots and mass spectrometry.
E.Carletti, J.P.Colletier, L.M.Schopfer, G.Santoni, P.Masson, O.Lockridge, F.Nachon, M.Weik.
 
  ABSTRACT  
 
Tri-o-cresyl-phosphate (TOCP) is a common additive in jet engine lubricants and hydraulic fluids suspected to have a role in aerotoxic syndrome in humans. TOCP is metabolized to cresyl saligenin phosphate (CBDP), a potent irreversible inhibitor of butyrylcholinesterase (BChE), a natural bioscavenger present in the bloodstream, and acetylcholinesterase (AChE), the off-switch at cholinergic synapses. Mechanistic details of cholinesterase (ChE) inhibition have, however, remained elusive. Also, the inhibition of AChE by CBDP is unexpected, from a structural standpoint, i.e., considering the narrowness of AChE active site and the bulkiness of CBDP. In the following, we report on kinetic X-ray crystallography experiments that provided 2.7-3.3 Å snapshots of the reaction of CBDP with mouse AChE and human BChE. The series of crystallographic snapshots reveals that AChE and BChE react with the opposite enantiomers and that an induced-fit rearrangement of Phe297 enlarges the active site of AChE upon CBDP binding. Mass spectrometry analysis of aging in either H(2)(16)O or H(2)(18)O furthermore allowed us to identify the inhibition steps, in which water molecules are involved, thus providing insights into the mechanistic details of inhibition. X-ray crystallography and mass spectrometry show the formation of an aged end product formed in both AChE and BChE that cannot be reactivated by current oxime-based therapeutics. Our study thus shows that only prophylactic and symptomatic treatments are viable to counter the inhibition of AChE and BChE by CBDP.