spacer
spacer

PDBsum entry 2gyw

Go to PDB code: 
protein ligands Protein-protein interface(s) links
Hydrolase PDB id
2gyw
Jmol
Contents
Protein chains
535 a.a. *
Ligands
NAG-FUC
NAG ×2
CO3 ×2
OBI ×2
P6G
Waters ×368
* Residue conservation analysis
PDB id:
2gyw
Name: Hydrolase
Title: Crystal structure of mus musculus acetylcholinesterase in co obidoxime
Structure: Acetylcholinesterase. Chain: a, b. Synonym: ache. Engineered: yes
Source: Mus musculus. House mouse. Organism_taxid: 10090. Gene: ache. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: embryonic kidney cells hek293f
Resolution:
2.40Å     R-factor:   0.197     R-free:   0.232
Authors: Y.P.Pang,M.Boman,E.Artursson,C.Akfur,S.Lundberg
Key ref: F.Ekström et al. (2006). Crystal structures of acetylcholinesterase in complex with HI-6, Ortho-7 and obidoxime: structural basis for differences in the ability to reactivate tabun conjugates. Biochem Pharmacol, 72, 597-607. PubMed id: 16876764
Date:
10-May-06     Release date:   15-Aug-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
Bound ligand (Het Group name = NAG)
matches with 41.18% 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   12 terms 
  Biological process     cell adhesion   9 terms 
  Biochemical function     carboxylic ester hydrolase activity     10 terms  

 

 
    reference    
 
 
Biochem Pharmacol 72:597-607 (2006)
PubMed id: 16876764  
 
 
Crystal structures of acetylcholinesterase in complex with HI-6, Ortho-7 and obidoxime: structural basis for differences in the ability to reactivate tabun conjugates.
F.Ekström, Y.P.Pang, M.Boman, E.Artursson, C.Akfur, S.Börjegren.
 
  ABSTRACT  
 
Inhibition of acetylcholinesterase (AChE) by organophosphorus compounds (OPs) such as pesticides and nerve agents causes acute toxicity or death of the intoxicated individual. The inhibited AChE may be reactivated by certain oximes as antidotes for clinical treatment of OP-intoxications. Crystal structures of the oximes HI-6, Ortho-7 and obidoxime in complex with Mus musculus acetylcholinesterase (mAChE) reveal different roles of the peripheral anionic site (PAS) in the binding of the oximes. A limited structural change of the side chains of Trp286 and Asp74 facilitates the intercalation of the 4-carboxylamide pyridinium ring of HI-6 between the side chains of Tyr124 and Trp286. The 2-carboxyimino pyridinium ring of HI-6 is accommodated at the entrance of the catalytic site with the oximate forming a hydrogen bond to the main-chain nitrogen atom of Phe295. In contrast to HI-6, the coordination of Ortho-7 and obidoxime within the PAS is facilitated by an extended structural change of Trp286 that allows one of the carboxyimino pyridinium rings to form a cation-pi interaction with the aromatic groups of Tyr72 and Trp286. The central chain of Ortho-7 and obidoxime is loosely coordinated in the active-site gorge, whereas the second carboxyimino pyridinium ring is accommodated in the vicinity of the phenol ring of Tyr337. The structural data clearly show analogous coordination of Ortho-7 and obidoxime within the active-site gorge of AChE. Different ability to reactivate AChE inhibited by tabun is shown in end-point reactivation experiments where HI-6, Ortho-7 and obidoxime showed an efficiency of 1, 45 and 38%, respectively. The low efficiency of HI-6 and the significantly higher efficiency of Ortho-7 and obidoxime may be explained by the differential binding of the oximes in the PAS and active-site gorge of AChE.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21397501 M.Komloova, K.Musilek, A.Horova, O.Holas, V.Dohnal, F.Gunn-Moore, and K.Kuca (2011).
Preparation, in vitro screening and molecular modelling of symmetrical bis-quinolinium cholinesterase inhibitors--implications for early myasthenia gravis treatment.
  Bioorg Med Chem Lett, 21, 2505-2509.  
20140002 M.K.Kesharwani, B.Ganguly, A.Das, and T.Bandyopadhyay (2010).
Differential binding of bispyridinium oxime drugs with acetylcholinesterase.
  Acta Pharmacol Sin, 31, 313-328.  
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
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
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.  
18359854 Y.Xu, J.P.Colletier, H.Jiang, I.Silman, J.L.Sussman, and M.Weik (2008).
Induced-fit or preexisting equilibrium dynamics? Lessons from protein crystallography and MD simulations on acetylcholinesterase and implications for structure-based drug design.
  Protein Sci, 17, 601-605.  
18502801 Y.Xu, J.P.Colletier, M.Weik, H.Jiang, J.Moult, I.Silman, and J.L.Sussman (2008).
Flexibility of aromatic residues in the active-site gorge of acetylcholinesterase: X-ray versus molecular dynamics.
  Biophys J, 95, 2500-2511.  
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
17562604 Z.Kovarik, M.Calić, G.Sinko, and A.Bosak (2007).
Structure-activity approach in the reactivation of tabun-phosphorylated human acetylcholinesterase with bispyridinium para-aldoximes.
  Arh Hig Rada Toksikol, 58, 201-209.  
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.