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PDBsum entry 1hbj

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protein ligands links
Hydrolase PDB id
1hbj
Jmol
Contents
Protein chain
532 a.a. *
Ligands
NAG
NAG-NAG
FBQ
MES
PG4
Waters ×171
* Residue conservation analysis
PDB id:
1hbj
Name: Hydrolase
Title: X-ray crystal structure of complex between torpedo californi ache and a reversible inhibitor, 4-amino-5-fluoro-2-methyl- (3-trifluoroacetylbenzylthiomethyl)quinoline
Structure: Acetylcholinesterase. Chain: a. Fragment: gpi-anchor removed, residues 22-564. Ec: 3.1.1.7
Source: Torpedo californica. Pacific electric ray. Organism_taxid: 7787. Variant: g2 form. Organ: electric organ. Tissue: electroplaque
Resolution:
2.50Å     R-factor:   0.183     R-free:   0.214
Authors: H.M.Greenblatt,G.Kryger,T.L.Lewis,C.Doucet-Personeni, R.Viner,I.Silman,J.L.Sussman
Key ref: C.Doucet-Personeni et al. (2001). A structure-based design approach to the development of novel, reversible AChE inhibitors. J Med Chem, 44, 3203-3215. PubMed id: 11563919 DOI: 10.1021/jm010826r
Date:
16-Apr-01     Release date:   25-Sep-01    
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/jm010826r J Med Chem 44:3203-3215 (2001)
PubMed id: 11563919  
 
 
A structure-based design approach to the development of novel, reversible AChE inhibitors.
C.Doucet-Personeni, P.D.Bentley, R.J.Fletcher, A.Kinkaid, G.Kryger, B.Pirard, A.Taylor, R.Taylor, J.Taylor, R.Viner, I.Silman, J.L.Sussman, H.M.Greenblatt, T.Lewis.
 
  ABSTRACT  
 
Chimeras of tacrine and m-(N,N,N-Trimethylammonio)trifluoroacetophenone (1) were designed as novel, reversible inhibitors of acetylcholinesterase. On the basis of the X-ray structure of the apoenzyme, a molecular modeling study determined the favored attachment positions on the 4-aminoquinoline ring (position 3 and the 4-amino nitrogen) and the favored lengths of a polymethylene link between the two moieties (respectively 5-6 and 4-5 sp(3) atoms). Seven compounds matching these criteria were synthesized, and their inhibitory potencies were determined to be in the low nanomolar range. Activity data for close analogues lacking some of the postulated key features showed that our predictions were correct. In addition, a subsequent crystal structure of acetylcholinesterase complexed with the most active compound 27 was in good agreement with our model. The design strategy is therefore validated and can now be developed further.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
17511008 T.Tian, X.C.Weng, Y.Song, L.X.Zhang, X.Zhou, and Y.Wang (2007).
Medicinal studies of dimeric phenols with multiple quaternary-ammonium pendant arms.
  Chem Biodivers, 4, 947-954.  
15473666 H.A.Jung, H.Y.Chung, T.Yokozawa, Y.C.Kim, S.K.Hyun, and J.S.Choi (2004).
Alaternin and emodin with hydroxyl radical inhibitory and/or scavenging activities and hepatoprotective activity on tacrine-induced cytotoxicity in HepG2 cells.
  Arch Pharm Res, 27, 947-953.  
12413557 P.Kuhn, K.Wilson, M.G.Patch, and R.C.Stevens (2002).
The genesis of high-throughput structure-based drug discovery using protein crystallography.
  Curr Opin Chem Biol, 6, 704-710.  
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