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PDBsum entry 3zlv

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protein ligands Protein-protein interface(s) links
Hydrolase PDB id
3zlv
Jmol
Contents
Protein chains
535 a.a.
Ligands
HI6 ×2
CO3
1KA ×5
PE4
Waters ×676
PDB id:
3zlv
Name: Hydrolase
Title: Crystal structure of mouse acetylcholinesterase in complex with tabun and hi-6
Structure: Acetylcholinesterase. Chain: a, b. Fragment: catalytic domain, residues 32-574. Synonym: ache. Engineered: yes. Other_details: catalytic ser203 phosphoamidated by tabun
Source: Mus musculus. House mouse. Organism_taxid: 10090. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293f
Resolution:
2.50Å     R-factor:   0.177     R-free:   0.225
Authors: E.Artursson,P.O.Andersson,C.Akfur,A.Linusson,S.Borjegren,F.E
Key ref: E.Artursson et al. (2013). Catalytic-site conformational equilibrium in nerve-agent adducts of acetylcholinesterase: possible implications for the HI-6 antidote substrate specificity. Biochem Pharmacol, 85, 1389-1397. PubMed id: 23376121 DOI: 10.1016/j.bcp.2013.01.016
Date:
04-Feb-13     Release date:   27-Mar-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P21836  (ACES_MOUSE) -  Acetylcholinesterase
Seq:
Struc:
 
Seq:
Struc:
614 a.a.
535 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.3.1.1.7  - Acetylcholinesterase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Acetylcholine + H2O = choline + acetate
Acetylcholine
Bound ligand (Het Group name = 1KA)
matches with 41.67% 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.2013.01.016 Biochem Pharmacol 85:1389-1397 (2013)
PubMed id: 23376121  
 
 
Catalytic-site conformational equilibrium in nerve-agent adducts of acetylcholinesterase: possible implications for the HI-6 antidote substrate specificity.
E.Artursson, P.O.Andersson, C.Akfur, A.Linusson, S.Börjegren, F.Ekström.
 
  ABSTRACT  
 
Nerve agents such as tabun, cyclosarin and Russian VX inhibit the essential enzyme acetylcholinesterase (AChE) by organophosphorylating the catalytic serine residue. Nucleophiles, such as oximes, are used as antidotes as they can reactivate and restore the function of the inhibited enzyme. The oxime HI-6 shows a notably low activity on tabun adducts but can effectively reactivate adducts of cyclosarin and Russian VX. To examine the structural basis for the pronounced substrate specificity of HI-6, we determined the binary crystal structures of Mus musculus AChE (mAChE) conjugated by cyclosarin and Russian VX and found a conformational mobility of the side chains of Phe338 and His447. The interaction between HI-6 and tabun-adducts of AChE were subsequently investigated using a combination of time resolved fluorescence spectroscopy and X-ray crystallography. Our findings show that HI-6 binds to tabun inhibited Homo sapiens AChE (hAChE) with an IC50 value of 300μM and suggest that the reactive nucleophilic moiety of HI-6 is excluded from the phosphorus atom of tabun. We propose that a conformational mobility of the side-chains of Phe338 and His447 is a common feature in nerve-agent adducts of AChE. We also suggest that the conformational mobility allow HI-6 to reactivate conjugates of cyclosarin and Russian VX while a reduced mobility in tabun conjugated AChE results in steric hindrance that prevents efficient reactivation.