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PDBsum entry 2jgj

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protein ligands Protein-protein interface(s) links
Hydrolase PDB id
2jgj
Jmol
Contents
Protein chains
536 a.a. *
Ligands
NAG ×2
AE3
P6G
Waters ×177
* Residue conservation analysis
PDB id:
2jgj
Name: Hydrolase
Title: Crystal structure of mouse acetylcholinesterase inhibited by methamidophos
Structure: Acetylcholinesterase. Chain: a, b. Fragment: catalytic domain, residues 32-574. Synonym: ache. Engineered: yes
Source: Mus musculus. Mouse. Organism_taxid: 10090. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293f.
Resolution:
2.50Å     R-factor:   0.214     R-free:   0.244
Authors: A.Hornberg,A.-K.Tunemalm,F.Ekstrom
Key ref: A.Hörnberg et al. (2007). Crystal structures of acetylcholinesterase in complex with organophosphorus compounds suggest that the acyl pocket modulates the aging reaction by precluding the formation of the trigonal bipyramidal transition state. Biochemistry, 46, 4815-4825. PubMed id: 17402711 DOI: 10.1021/bi0621361
Date:
13-Feb-07     Release date:   17-Apr-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P21836  (ACES_MOUSE) -  Acetylcholinesterase
Seq:
Struc:
 
Seq:
Struc:
614 a.a.
536 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 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 41.18% 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/bi0621361 Biochemistry 46:4815-4825 (2007)
PubMed id: 17402711  
 
 
Crystal structures of acetylcholinesterase in complex with organophosphorus compounds suggest that the acyl pocket modulates the aging reaction by precluding the formation of the trigonal bipyramidal transition state.
A.Hörnberg, A.K.Tunemalm, F.Ekström.
 
  ABSTRACT  
 
Organophosphorus compounds (OPs), such as nerve agents and a group of insecticides, irreversibly inhibit the enzyme acetylcholinesterase (AChE) by a rapid phosphorylation of the catalytic Ser203 residue. The formed AChE-OP conjugate subsequently undergoes an elimination reaction, termed aging, that results in an enzyme completely resistant to oxime-mediated reactivation by medical antidotes. In this study, we present crystal structures of the non-aged and aged complexes between Mus musculus AChE (mAChE) and the nerve agents sarin, VX, and diisopropyl fluorophosphate (DFP) and the OP-based insecticides methamidophos (MeP) and fenamiphos (FeP). Non-aged conjugates of MeP, sarin, and FeP and aged conjugates of MeP, sarin, and VX are very similar to the noninhibited apo conformation of AChE. A minor structural change in the side chain of His447 is observed in the non-aged conjugate of VX. In contrast, an extensive rearrangement of the acyl loop region (residues 287-299) is observed in the non-aged structure of DFP and in the aged structures of DFP and FeP. In the case of FeP, the relatively large substituents of the phosphorus atom are reorganized during aging, providing a structural support of an aging reaction that proceeds through a nucleophilic attack on the phosphorus atom. The FeP aging rate constant is 14 times lower than the corresponding constant for the structurally related OP insecticide MeP, suggesting that tight steric constraints of the acyl pocket loop preclude the formation of a trigonal bipyramidal intermediate.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20058292 K.Musilek, O.Holas, J.Misik, M.Pohanka, L.Novotny, V.Dohnal, V.Opletalova, and K.Kuca (2010).
Monooxime-monocarbamoyl Bispyridinium Xylene-Linked Reactivators of Acetylcholinesterase-Synthesis, In vitro and Toxicity Evaluation, and Docking Studies.
  ChemMedChem, 5, 247-254.  
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
19924840 J.Liu, Y.Zhang, and C.G.Zhan (2009).
Reaction pathway and free-energy barrier for reactivation of dimethylphosphoryl-inhibited human acetylcholinesterase.
  J Phys Chem B, 113, 16226-16236.  
19271773 T.M.Epstein, U.Samanta, S.D.Kirby, D.M.Cerasoli, and B.J.Bahnson (2009).
Crystal structures of brain group-VIII phospholipase A2 in nonaged complexes with the organophosphorus nerve agents soman and sarin.
  Biochemistry, 48, 3425-3435.
PDB codes: 3dt6 3dt8 3dt9
19394314 U.Samanta, S.D.Kirby, P.Srinivasan, D.M.Cerasoli, and B.J.Bahnson (2009).
Crystal structures of human group-VIIA phospholipase A2 inhibited by organophosphorus nerve agents exhibit non-aged complexes.
  Biochem Pharmacol, 78, 420-429.
PDB codes: 3f96 3f97 3f98 3f9c
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
19402731 Y.Pan, J.L.Muzyka, and C.G.Zhan (2009).
Model of human butyrylcholinesterase tetramer by homology modeling and dynamics simulation.
  J Phys Chem B, 113, 6543-6552.  
18422653 P.Masson, M.T.Froment, E.Gillon, F.Nachon, O.Lockridge, and L.M.Schopfer (2008).
Kinetic analysis of effector modulation of butyrylcholinesterase-catalysed hydrolysis of acetanilides and homologous esters.
  FEBS J, 275, 2617-2631.  
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 codes are shown on the right.