spacer
spacer

PDBsum entry 2wu3

Go to PDB code: 
protein ligands Protein-protein interface(s) links
Hydrolase PDB id
2wu3
Jmol
Contents
Protein chains
539 a.a. *
Ligands
HI6 ×2
NAG ×2
P6G
CO3 ×2
Waters ×291
* Residue conservation analysis
PDB id:
2wu3
Name: Hydrolase
Title: Crystal structure of mouse acetylcholinesterase in complex with fenamiphos and hi-6
Structure: Acetylcholinesterase. Chain: a, b. Fragment: catalytic domain, residues 32-574. Engineered: yes. Other_details: fenamiphos covalently bound to ser203
Source: Mus musculus. Mouse. Organism_taxid: 10090. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293f.
Resolution:
2.70Å     R-factor:   0.172     R-free:   0.226
Authors: A.Hornberg,E.Artursson,R.Warme,Y.-P.Pang,F.Ekstrom
Key ref: A.Hörnberg et al. (2010). Crystal structures of oxime-bound fenamiphos-acetylcholinesterases: reactivation involving flipping of the His447 ring to form a reactive Glu334-His447-oxime triad. Biochem Pharmacol, 79, 507-515. PubMed id: 19732756 DOI: 10.1016/j.bcp.2009.08.027
Date:
28-Sep-09     Release date:   20-Oct-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P21836  (ACES_MOUSE) -  Acetylcholinesterase
Seq:
Struc:
 
Seq:
Struc:
614 a.a.
539 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 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 41.00% similarity
+ H(2)O
= choline
+
acetate
Bound ligand (Het Group name = CO3)
matches with 60.00% similarity
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: 10.1016/j.bcp.2009.08.027 Biochem Pharmacol 79:507-515 (2010)
PubMed id: 19732756  
 
 
Crystal structures of oxime-bound fenamiphos-acetylcholinesterases: reactivation involving flipping of the His447 ring to form a reactive Glu334-His447-oxime triad.
A.Hörnberg, E.Artursson, R.Wärme, Y.P.Pang, F.Ekström.
 
  ABSTRACT  
 
Organophosphorus insecticides and nerve agents inhibit the vital enzyme acetylcholinesterase by covalently bonding to the catalytic serine residue of the enzyme. Oxime-based reactivators, such as [(E)-[1-[(4-carbamoylpyridin-1-ium-1-yl)methoxymethyl]pyridin-2-ylidene]methyl]-oxoazanium dichloride (HI-6) and 1,7-heptylene-bis-N,N'-2-pyridiniumaldoxime dichloride (Ortho-7), restore the organophosphate-inhibited enzymatic activity by cleaving the phosphorous conjugate. In this article, we report the intermolecular interactions between Mus musculus acetylcholinesterase inhibited by the insecticide fenamiphos (fep-mAChE) and HI-6 or Ortho-7 revealed by a combination of crystallography and kinetics. The crystal structures of the two oxime-bound fep-mAChE complexes show that both oximes interact with the peripheral anionic site involving different conformations of Trp286 and different peripheral-site residues (Tyr124 for HI-6 and Tyr72 for Ortho-7). Moreover, residues at catalytic site of the HI-6-bound fep-mAChE complex adopt conformations that are similar to those in the apo mAChE, whereas significant conformational changes are observed for the corresponding residues in the Ortho-7-bound fep-mAChE complex. Interestingly, flipping of the His447 imidazole ring allows the formation of a hydrogen bonding network among the Glu334-His447-Ortho-7 triad, which presumably deprotonates the Ortho-7 oxime hydroxyl group, increases the nucleophilicity of the oxime group, and leads to cleavage of the phosphorous conjugate. These results offer insights into a detailed reactivation mechanism for the oximes and development of improved reactivators.