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PDBsum entry 2ckm

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protein ligands links
Hydrolase PDB id
2ckm
Jmol
Contents
Protein chain
528 a.a. *
Ligands
AA7
NAG ×2
Waters ×206
* Residue conservation analysis
PDB id:
2ckm
Name: Hydrolase
Title: Torpedo californica acetylcholinesterase complexed with alkylene-linked bis-tacrine dimer (7 carbon linker)
Structure: Acetylcholinesterase. Chain: a. Synonym: ache. Ec: 3.1.1.7
Source: Torpedo californica. Pacific electric ray. Organism_taxid: 7787. Variant: g2 form. Organ: electric organ. Tissue: electroplaque
Biol. unit: Dimer (from PDB file)
Resolution:
2.15Å     R-factor:   0.211     R-free:   0.249
Authors: B.Brumshtein,E.H.Rydberg,H.M.Greenblatt,D.M.Wong,D.Shaya, L.D.Williams,P.R.Carlier,Y.P.Pang,I.Silman,J.L.Sussman
Key ref: E.H.Rydberg et al. (2006). Complexes of alkylene-linked tacrine dimers with Torpedo californica acetylcholinesterase: Binding of Bis5-tacrine produces a dramatic rearrangement in the active-site gorge. J Med Chem, 49, 5491-5500. PubMed id: 16942022 DOI: 10.1021/jm060164b
Date:
20-Apr-06     Release date:   04-Sep-06    
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 41.00% 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     synapse   5 terms 
  Biological process     neurotransmitter catabolic process   2 terms 
  Biochemical function     carboxylic ester hydrolase activity     4 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm060164b J Med Chem 49:5491-5500 (2006)
PubMed id: 16942022  
 
 
Complexes of alkylene-linked tacrine dimers with Torpedo californica acetylcholinesterase: Binding of Bis5-tacrine produces a dramatic rearrangement in the active-site gorge.
E.H.Rydberg, B.Brumshtein, H.M.Greenblatt, D.M.Wong, D.Shaya, L.D.Williams, P.R.Carlier, Y.P.Pang, I.Silman, J.L.Sussman.
 
  ABSTRACT  
 
The X-ray crystal structures were solved for complexes with Torpedo californica acetylcholinesterase of two bivalent tacrine derivative compounds in which the two tacrine rings were separated by 5- and 7-carbon spacers. The derivative with the 7-carbon spacer spans the length of the active-site gorge, making sandwich interactions with aromatic residues both in the catalytic anionic site (Trp84 and Phe330) at the bottom of the gorge and at the peripheral anionic site near its mouth (Tyr70 and Trp279). The derivative with the 5-carbon spacer interacts in a similar manner at the bottom of the gorge, but the shorter tether precludes a sandwich interaction at the peripheral anionic site. Although the upper tacrine group does interact with Trp279, it displaces the phenyl residue of Phe331, thus causing a major rearrangement in the Trp279-Ser291 loop. The ability of this inhibitor to induce large-scale structural changes in the active-site gorge of acetylcholinesterase has significant implications for structure-based drug design because such conformational changes in the target enzyme are difficult to predict and to model.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21152577 M.Ouberai, K.Brannstrom, M.Vestling, A.Olofsson, P.Dumy, S.Chierici, and J.Garcia (2011).
Clicked tacrine conjugates as acetylcholinesterase and β-amyloid directed compounds.
  Org Biomol Chem, 9, 1140-1147.  
21367493 Y.P.Li, F.X.Ning, M.B.Yang, Y.C.Li, M.H.Nie, T.M.Ou, J.H.Tan, S.L.Huang, D.Li, L.Q.Gu, and Z.S.Huang (2011).
Syntheses and characterization of novel oxoisoaporphine derivatives as dual inhibitors for cholinesterases and amyloid beta aggregation.
  Eur J Med Chem, 46, 1572-1581.  
20486153 M.L.Bolognesi, M.Bartolini, F.Mancini, G.Chiriano, L.Ceccarini, M.Rosini, A.Milelli, V.Tumiatti, V.Andrisano, and C.Melchiorre (2010).
Bis(7)-tacrine derivatives as multitarget-directed ligands: Focus on anticholinesterase and antiamyloid activities.
  ChemMedChem, 5, 1215-1220.  
20190520 O.Takahashi, Y.Masuda, A.Muroya, and T.Furuya (2010).
[In-silico approaches for fragment-based drug design].
  Yakugaku Zasshi, 130, 349-354.  
18471807 A.Shafferman, D.Barak, D.Stein, C.Kronman, B.Velan, N.H.Greig, and A.Ordentlich (2008).
Flexibility versus "rigidity" of the functional architecture of AChE active center.
  Chem Biol Interact, 175, 166-172.  
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.  
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