spacer
spacer

PDBsum entry 2bag

Go to PDB code: 
protein ligands links
Hydrolase PDB id
2bag
Jmol
Contents
Protein chain
532 a.a. *
Ligands
NAG ×2
1PE
GSG
MES ×2
Waters ×274
* Residue conservation analysis
PDB id:
2bag
Name: Hydrolase
Title: 3d structure of torpedo californica acetylcholinesterase com with ganstigmine
Structure: Acetylcholinesterase. Chain: a. Synonym: ache. Ec: 3.1.1.7
Source: Torpedo californica. Pacific electric ray. Organism_taxid: 7787. Variant: g2 form. Organ: eletric organ. Tissue: electroplaque
Resolution:
2.40Å     R-factor:   0.190     R-free:   0.236
Authors: D.Lamba,C.Bartolucci,M.Siotto,M.Racchi,G.Villetti,M.Delcanal
Key ref: C.Bartolucci et al. (2006). Structural determinants of Torpedo californica acetylcholinesterase inhibition by the novel and orally active carbamate based anti-alzheimer drug ganstigmine (CHF-2819). J Med Chem, 49, 5051-5058. PubMed id: 16913695 DOI: 10.1021/jm060293s
Date:
14-Oct-05     Release date:   29-Aug-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P04058  (ACES_TORCA) -  Acetylcholinesterase
Seq:
Struc:
 
Seq:
Struc:
586 a.a.
532 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
Bound ligand (Het Group name = MES)
matches with 46.15% similarity
+ acetate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     synapse   5 terms 
  Biological process     neurotransmitter catabolic process   2 terms 
  Biochemical function     carboxylic ester hydrolase activity     4 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm060293s J Med Chem 49:5051-5058 (2006)
PubMed id: 16913695  
 
 
Structural determinants of Torpedo californica acetylcholinesterase inhibition by the novel and orally active carbamate based anti-alzheimer drug ganstigmine (CHF-2819).
C.Bartolucci, M.Siotto, E.Ghidini, G.Amari, P.T.Bolzoni, M.Racchi, G.Villetti, M.Delcanale, D.Lamba.
 
  ABSTRACT  
 
Ganstigmine is an orally active, geneserine derived, carbamate-based acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. The crystal structure of the ganstigmine conjugate with Torpedo californica acetylcholinesterase (TcAChE) has been determined at 2.40 A resolution, and a detailed structure-based analysis of the in vitro and ex vivo anti-AChE activity by ganstigmine and by new geneserine derivatives is presented. The carbamoyl moiety is covalently bound to the active-site serine, whereas the leaving group geneseroline is not retained in the catalytic pocket. The nitrogen atom of the carbamoyl moiety of ganstigmine is engaged in a key hydrogen-bonding interaction with the active site histidine (His440). This result offers an explanation for the inactivation of the catalytic triad and may account for the long duration of action of ganstigmine in vivo. The 3D structure also provides a structural framework for the design of compounds with improved binding affinity and pharmacological properties.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
18729824 D.Barak, A.Ordentlich, D.Stein, Q.S.Yu, N.H.Greig, and A.Shafferman (2009).
Accommodation of physostigmine and its analogues by acetylcholinesterase is dominated by hydrophobic interactions.
  Biochem J, 417, 213-222.  
18972573 H.K.Vaddi, S.L.Banks, J.Chen, D.C.Hammell, P.A.Crooks, and A.L.Stinchcomb (2009).
Human skin permeation of 3-O-alkyl carbamate prodrugs of naltrexone.
  J Pharm Sci, 98, 2611-2625.  
19292865 M.Pietsch, L.Christian, T.Inhester, S.Petzold, and M.Gütschow (2009).
Kinetics of inhibition of acetylcholinesterase in the presence of acetonitrile.
  FEBS J, 276, 2292-2307.  
18284552 A.Siwicka, Z.Moleda, K.Wojtasiewicz, A.Zawadzka, J.K.Maurin, M.Panasiewicz, T.Pacuszka, and Z.Czarnocki (2008).
The oxidation products of melatonin derivatives exhibit acetylcholinesterase and butyrylcholinesterase inhibitory activity.
  J Pineal Res, 45, 40-49.  
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.