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PDBsum entry 2w6c

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protein ligands links
Hydrolase PDB id
2w6c
Jmol
Contents
Protein chain
528 a.a. *
Ligands
BM4
NAG ×2
NAG-NAG
Waters ×115
* Residue conservation analysis
PDB id:
2w6c
Name: Hydrolase
Title: Ache in complex with a bis-(-)-nor-meptazinol derivative
Structure: Acetylcholinesterase. Chain: x. Synonym: ache. Ec: 3.1.1.7
Source: Torpedo californica. Pacific electric ray. Organism_taxid: 7787. Organ: electric organ
Resolution:
2.69Å     R-factor:   0.188     R-free:   0.235
Authors: A.Paz,Q.Xie,H.M.Greenblatt,W.Fu,Y.Tang,I.Silman,Z.Qiu, J.L.Sussman
Key ref: A.Paz et al. (2009). The crystal structure of a complex of acetylcholinesterase with a bis-(-)-nor-meptazinol derivative reveals disruption of the catalytic triad. J Med Chem, 52, 2543-2549. PubMed id: 19326912 DOI: 10.1021/jm801657v
Date:
18-Dec-08     Release date:   07-Apr-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P04058  (ACES_TORCA) -  Acetylcholinesterase
Seq:
Struc:
 
Seq:
Struc:
586 a.a.
528 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
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     acetylcholine catabolic process in synaptic cleft   1 term 
  Biochemical function     acetylcholinesterase activity     2 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm801657v J Med Chem 52:2543-2549 (2009)
PubMed id: 19326912  
 
 
The crystal structure of a complex of acetylcholinesterase with a bis-(-)-nor-meptazinol derivative reveals disruption of the catalytic triad.
A.Paz, Q.Xie, H.M.Greenblatt, W.Fu, Y.Tang, I.Silman, Z.Qiu, J.L.Sussman.
 
  ABSTRACT  
 
A bis-(-)-nor-meptazinol derivative in which the two meptazinol rings are linked by a nonamethylene spacer is a novel acetylcholinesterase inhibitor that inhibits both catalytic activity and Abeta peptide aggregation. The crystal structure of its complex with Torpedo californica acetylcholinesterase was determined to 2.7 A resolution. The ligand spans the active-site gorge, with one nor-meptazinol moiety bound at the "anionic" subsite of the active site, disrupting the catalytic triad by forming a hydrogen bond with His440N(epsilon2), which is hydrogen-bonded to Ser200O(gamma) in the native enzyme. The second nor-meptazinol binds at the peripheral "anionic" site at the gorge entrance. A number of GOLD models of the complex, using both native TcAChE and the protein template from the crystal structure of the bis-(-)-nor-meptazinol/TcAChE complex, bear higher similarity to the X-ray structure than a previous model obtained using the mouse enzyme structure. These findings may facilitate rational design of new meptazinol-based acetylcholinesterase inhibitors.