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PDBsum entry 2c0q

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protein ligands Protein-protein interface(s) links
Hydrolase PDB id
2c0q
Jmol
Contents
Protein chains
535 a.a. *
Ligands
NTJ ×2
P6G
Waters ×231
* Residue conservation analysis
PDB id:
2c0q
Name: Hydrolase
Title: Non-aged form of mouse acetylcholinesterase inhibited by tabun
Structure: Acetylcholinesterase. Chain: a, b. Fragment: catalytic domain, residues 32-574. Engineered: yes. Other_details: tabun reaction product covalently attached to ser203
Source: Mus musculus. Mouse. Organism_taxid: 10090. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293f.
Resolution:
2.5Å     R-factor:   0.197     R-free:   0.246
Authors: F.Ekstrom,C.Akfur,A.-K.Tunemalm,S.Lundberg
Key ref:
F.Ekström et al. (2006). Structural changes of phenylalanine 338 and histidine 447 revealed by the crystal structures of tabun-inhibited murine acetylcholinesterase. Biochemistry, 45, 74-81. PubMed id: 16388582 DOI: 10.1021/bi051286t
Date:
07-Sep-05     Release date:   09-Jan-06    
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

 Enzyme reactions 
   Enzyme class: E.C.3.1.1.7  - Acetylcholinesterase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Acetylcholine + H2O = choline + acetate
Acetylcholine
+ 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/bi051286t Biochemistry 45:74-81 (2006)
PubMed id: 16388582  
 
 
Structural changes of phenylalanine 338 and histidine 447 revealed by the crystal structures of tabun-inhibited murine acetylcholinesterase.
F.Ekström, C.Akfur, A.K.Tunemalm, S.Lundberg.
 
  ABSTRACT  
 
Organophosphorus compounds (OPs) interfere with the catalytic mechanism of acetylcholinesterase (AChE) by rapidly phosphorylating the catalytic serine residue. The inhibited enzyme can at least partly be reactivated with nucleophilic reactivators such as oximes. The covalently attached OP conjugate may undergo further intramolecular dealkylation or deamidation reactions, a process termed "aging" that results in an enzyme considered completely resistant to reactivation. Of particular interest is the inhibition and aging reaction of the OP compound tabun since tabun conjugates display an extraordinary resistance toward most reactivators of today. To investigate the structural basis for this resistance, we determined the crystal structures of Mus musculus AChE (mAChE) inhibited by tabun prior to and after the aging reaction. The nonaged tabun conjugate induces a structural change of the side chain of His447 that uncouples the catalytic triad and positions the imidazole ring of His447 in a conformation where it may form a hydrogen bond to a water molecule. Moreover, an unexpected displacement of the side chain of Phe338 narrows the active site gorge. In the crystal structure of the aged tabun conjugate, the side chains of His447 and Phe338 are reversed to the conformation found in the apo structure of mAChE. A hydrogen bond between the imidazole ring of His447 and the ethoxy oxygen of the aged tabun conjugate stabilizes the side chain of His447. The displacement of the side chain of Phe338 into the active site gorge of the nonaged tabun conjugate may interfere with the accessibility of reactivators and thereby contribute to the high resistance of tabun conjugates toward reactivation.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21142778 J.Kassa, J.Z.Karasova, R.Pavlikova, K.Musilek, K.Kuca, J.Bajgar, and Y.S.Jung (2011).
A comparison of reactivating and therapeutic efficacy of bispyridinium acetylcholinesterase reactivator KR-22934 with the oxime K203 and commonly used oximes (obidoxime, trimedoxime, HI-6) in tabun-poisoned rats and mice.
  Toxicol Mech Methods, 21, 241-245.  
  19724118 A.Brzuszkiewicz, E.Nowak, Z.Dauter, M.Dauter, H.Cieśliński, A.Długołecka, and J.Kur (2009).
Structure of EstA esterase from psychrotrophic Pseudoalteromonas sp. 643A covalently inhibited by monoethylphosphonate.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 65, 862-865.
PDB code: 3hp4
19536291 F.Ekström, A.Hörnberg, E.Artursson, L.G.Hammarström, G.Schneider, and Y.P.Pang (2009).
Structure of HI-6*sarin-acetylcholinesterase determined by X-ray crystallography and molecular dynamics simulation: reactivator mechanism and design.
  PLoS One, 4, e5957.
PDB codes: 2whp 2whq 2whr
19714254 Y.P.Pang, F.Ekström, G.A.Polsinelli, Y.Gao, S.Rana, D.H.Hua, B.Andersson, P.O.Andersson, L.Peng, S.K.Singh, R.K.Mishra, K.Y.Zhu, A.M.Fallon, D.W.Ragsdale, and S.Brimijoin (2009).
Selective and irreversible inhibitors of mosquito acetylcholinesterases for controlling malaria and other mosquito-borne diseases.
  PLoS One, 4, e6851.
PDB code: 2wls
18471807 A.Shafferman, D.Barak, D.Stein, C.Kronman, B.Velan, N.H.Greig, and A.Ordentlich (2008).
Flexibility versus "rigidity" of the functional architecture of AChE active center.
  Chem Biol Interact, 175, 166-172.  
18369602 K.Musilek, J.Jampilek, J.Dohnal, D.Jun, F.Gunn-Moore, M.Dolezal, and K.Kuca (2008).
RP-HPLC determination of the lipophilicity of bispyridinium reactivators of acetylcholinesterase bearing a but-2-ene connecting linker.
  Anal Bioanal Chem, 391, 367-372.  
17407327 C.D.Fleming, C.C.Edwards, S.D.Kirby, D.M.Maxwell, P.M.Potter, D.M.Cerasoli, and M.R.Redinbo (2007).
Crystal structures of human carboxylesterase 1 in covalent complexes with the chemical warfare agents soman and tabun.
  Biochemistry, 46, 5063-5071.
PDB codes: 2hrq 2hrr
17443135 F.J.Ekström, C.Astot, and Y.P.Pang (2007).
Novel nerve-agent antidote design based on crystallographic and mass spectrometric analyses of tabun-conjugated acetylcholinesterase in complex with antidotes.
  Clin Pharmacol Ther, 82, 282-293.
PDB codes: 2jey 2jez 2jf0
17577312 K.Kuca, D.Jun, J.Cabal, and L.Musilova (2007).
Bisquaternary oximes as reactivators of tabun-inhibited human brain cholinesterases: an in vitro study.
  Basic Clin Pharmacol Toxicol, 101, 25-28.  
17288500 T.C.Marrs, P.Rice, and J.A.Vale (2006).
The role of oximes in the treatment of nerve agent poisoning in civilian casualties.
  Toxicol Rev, 25, 297-323.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.