PDBsum entry 2wu4

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Hydrolase PDB id
Protein chains
530 a.a. *
HBP ×2
Waters ×325
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Crystal structure of mouse acetylcholinesterase in complex with fenamiphos and ortho-7
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.
2.40Å     R-factor:   0.186     R-free:   0.223
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
28-Sep-09     Release date:   20-Oct-09    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P21836  (ACES_MOUSE) -  Acetylcholinesterase
614 a.a.
530 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.  - Acetylcholinesterase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Acetylcholine + H2O = choline + acetate
Bound ligand (Het Group name = NAG)
matches with 41.00% 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   12 terms 
  Biological process     receptor internalization   8 terms 
  Biochemical function     carboxylic ester hydrolase activity     9 terms  


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.
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.