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PDBsum entry 1c2o

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protein Protein-protein interface(s) links
Hydrolase PDB id
1c2o
Jmol
Contents
Protein chains
539 a.a. *
* Residue conservation analysis
PDB id:
1c2o
Name: Hydrolase
Title: Electrophorus electricus acetylcholinesterase
Structure: Acetylcholinesterase. Chain: a, b, c, d. Fragment: a4 form. Other_details: see remark 450 for information regarding the and sequence
Source: Electrophorus electricus. Electric eel. Organism_taxid: 8005. Other_details: electric organ
Resolution:
4.20Å     R-factor:   0.375     R-free:   0.385
Authors: Y.Bourne,P.Marchot
Key ref:
Y.Bourne et al. (1999). Conformational flexibility of the acetylcholinesterase tetramer suggested by x-ray crystallography. J Biol Chem, 274, 30370-30376. PubMed id: 10521413 DOI: 10.1074/jbc.274.43.30370
Date:
26-Jul-99     Release date:   19-Jan-00    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P21836  (ACES_MOUSE) -  Acetylcholinesterase
Seq:
Struc:
 
Seq:
Struc:
614 a.a.
539 a.a.
Key:    PfamA domain  Secondary structure

 Enzyme reactions 
   Enzyme class: E.C.3.1.1.7  - Acetylcholinesterase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Acetylcholine + H2O = choline + acetate
Acetylcholine
+ 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     extracellular region   17 terms 
  Biological process     synapse assembly   13 terms 
  Biochemical function     carboxylic ester hydrolase activity     9 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.274.43.30370 J Biol Chem 274:30370-30376 (1999)
PubMed id: 10521413  
 
 
Conformational flexibility of the acetylcholinesterase tetramer suggested by x-ray crystallography.
Y.Bourne, J.Grassi, P.E.Bougis, P.Marchot.
 
  ABSTRACT  
 
Acetylcholinesterase, a polymorphic enzyme, appears to form amphiphilic and nonamphiphilic tetramers from a single splice variant; this suggests discrete tetrameric arrangements where the amphipathic carboxyl-terminal sequences can be either buried or exposed. Two distinct, but related crystal structures of the soluble, trypsin-released tetramer of acetylcholinesterase from Electrophorus electricus were solved at 4.5 and 4.2 A resolution by molecular replacement. Resolution at these levels is sufficient to provide substantial information on the relative orientations of the subunits within the tetramer. The two structures, which show canonical homodimers of subunits assembled through four-helix bundles, reveal discrete geometries in the assembly of the dimers to form: (a) a loose, pseudo-square planar tetramer with antiparallel alignment of the two four-helix bundles and a large space in the center where the carboxyl-terminal sequences may be buried or (b) a compact, square nonplanar tetramer that may expose all four sequences on a single side. Comparison of these two structures points to significant conformational flexibility of the tetramer about the four-helix bundle axis and along the dimer-dimer interface. Hence, in solution, several conformational states of a flexible tetrameric arrangement of acetylcholinesterase catalytic subunits may exist to accommodate discrete carboxyl-terminal sequences of variable dimensions and amphipathicity.
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. Alignment of the amino acid sequences of EeAChE and mAChE. The secondary structure motifs of mAChE (12, 18) are specified according to Ref. 45. The putative N-glycosylation sites of EeAChE (5) are indicated by black spheres.
Figure 3.
Fig. 3. Overall views of the loose, pseudo-square planar EeAChE tetramer A and the compact, square nonplanar EeAChE tetramer B. Top left, ribbon diagram of tetramer A viewed perpendicular to the four-helix bundle axis; top right, tetramer A viewed parallel to the four-helix bundle axis, 90° from the left view. Bottom left, ribbon diagram of tetramer B viewed perpendicular to the four-helix bundle axis of dimer AB (which is oriented as in the top left panel and is masked by dimer CD); bottom right, tetramer B viewed perpendicular to the dimer-dimer interface, 90° from the left view. The italicized labels A and B refer to the subunits in the left dimer and labels C and D to subunits in the right dimer for the top left and bottom right orientations. In tetramer A (overall dimensions: 132 × 132 × 55 Å), the main axes of the two dimers are tilted by ~40° from each other and the axes of the two four-helix bundles, made of helices 3[7,8] and [10] from two subunits and displayed in black, are aligned antiparallel with convergent helices [10]; the four peripheral sites, of which two from diagonally opposed subunits are oriented above the plane of the figure (circled), are accessible to the outside solvent; the apparent free space in the center of tetramer A is 75 Å long × 35 Å wide. In tetramer B (130 × 100 × 55 Å), the main axes of the two dimers are aligned antiparallel and the two four-helix bundle axes are positioned 60° from each other with convergent helices [10]; of the four peripheral sites, two are accessible to the outside solvent (circled) and two face the central, internal space (75 × 15 Å). For each of the two structures, the backbone shown is that of mAChE but residue numbering is that of EeAChE (cf. Fig. 2); the position of peptide Ile^418-Gln446, which is unique to EeAChE and has not been modeled, is indicated by an arrow; the putative N-glycosylation sites are indicated by black spheres; and the labels N and C indicate the amino and carboxyl termini of subunit A, respectively.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (1999, 274, 30370-30376) copyright 1999.  
  Figures were selected by the author.  
 
 
    Author's comment    
 
  Given the limited resolution of structures 1c2b and 1c20, the coordinates use the sequence of mouse AChE, that was used as a template for the molecular replacement procedure - see remark 999 in the PDB header records. (Note that for the related structure 1eea, solved by a different group, the sequence used was that of Torpedo AChE).
This protein forms a tetramer, thus for the 1c2b structure the biological unit needs to be rebuilt using the symmetry operators given in the PDB file.
Pascale Marchot
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20005727 S.B.Bharate, L.Guo, T.E.Reeves, D.M.Cerasoli, and C.M.Thompson (2010).
Bisquaternary pyridinium oximes: Comparison of in vitro reactivation potency of compounds bearing aliphatic linkers and heteroaromatic linkers for paraoxon-inhibited electric eel and recombinant human acetylcholinesterase.
  Bioorg Med Chem, 18, 787-794.  
19651048 A.A.Gorfe, B.Lu, Z.Yu, and J.A.McCammon (2009).
Enzymatic activity versus structural dynamics: the case of acetylcholinesterase tetramer.
  Biophys J, 97, 897-905.  
19292875 M.F.Montenegro, M.T.Moral-Naranjo, E.Muñoz-Delgado, F.J.Campoy, and C.J.Vidal (2009).
Hydrolysis of acetylthiocoline, o-nitroacetanilide and o-nitrotrifluoroacetanilide by fetal bovine serum acetylcholinesterase.
  FEBS J, 276, 2074-2083.  
19640713 S.B.Bharate, L.Guo, T.E.Reeves, D.M.Cerasoli, and C.M.Thompson (2009).
New series of monoquaternary pyridinium oximes: Synthesis and reactivation potency for paraoxon-inhibited electric eel and recombinant human acetylcholinesterase.
  Bioorg Med Chem Lett, 19, 5101-5104.  
19402731 Y.Pan, J.L.Muzyka, and C.G.Zhan (2009).
Model of human butyrylcholinesterase tetramer by homology modeling and dynamics simulation.
  J Phys Chem B, 113, 6543-6552.  
17921202 A.A.Gorfe, C.E.Chang, I.Ivanov, and J.A.McCammon (2008).
Dynamics of the acetylcholinesterase tetramer.
  Biophys J, 94, 1144-1154.  
17653279 L.Jean, B.Thomas, A.Tahiri-Alaoui, M.Shaw, and D.J.Vaux (2007).
Heterologous amyloid seeding: revisiting the role of acetylcholinesterase in Alzheimer's disease.
  PLoS ONE, 2, e652.  
  17768338 M.N.Ngamelue, K.Homma, O.Lockridge, and O.A.Asojo (2007).
Crystallization and X-ray structure of full-length recombinant human butyrylcholinesterase.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 723-727.
PDB code: 2pm8
16791318 G.Pastorin, S.Marchesan, J.Hoebeke, T.Da Ros, L.Ehret-Sabatier, J.P.Briand, M.Prato, and A.Bianco (2006).
Design and activity of cationic fullerene derivatives as inhibitors of acetylcholinesterase.
  Org Biomol Chem, 4, 2556-2562.  
16905105 N.Furnham, A.S.Doré, D.Y.Chirgadze, P.I.de Bakker, M.A.Depristo, and T.L.Blundell (2006).
Knowledge-based real-space explorations for low-resolution structure determination.
  Structure, 14, 1313-1320.  
17183688 Y.P.Pang (2006).
Novel acetylcholinesterase target site for malaria mosquito control.
  PLoS ONE, 1, e58.  
15994894 A.S.Ramos, and S.Techert (2005).
Influence of the water structure on the acetylcholinesterase efficiency.
  Biophys J, 89, 1990-2003.  
16299589 D.Zhang, and J.A.McCammon (2005).
The association of tetrameric acetylcholinesterase with ColQ tail: a block normal mode analysis.
  PLoS Comput Biol, 1, e62.  
15626705 D.Zhang, J.Suen, Y.Zhang, Y.Song, Z.Radic, P.Taylor, M.J.Holst, C.Bajaj, N.A.Baker, and J.A.McCammon (2005).
Tetrameric mouse acetylcholinesterase: continuum diffusion rate calculations by solving the steady-state Smoluchowski equation using finite element methods.
  Biophys J, 88, 1659-1665.  
16094692 H.Schmidinger, R.Birner-Gruenberger, G.Riesenhuber, R.Saf, H.Susani-Etzerodt, and A.Hermetter (2005).
Novel fluorescent phosphonic acid esters for discrimination of lipases and esterases.
  Chembiochem, 6, 1776-1781.  
15526038 H.Dvir, M.Harel, S.Bon, W.Q.Liu, M.Vidal, C.Garbay, J.L.Sussman, J.Massoulié, and I.Silman (2004).
The synaptic acetylcholinesterase tetramer assembles around a polyproline II helix.
  EMBO J, 23, 4394-4405.
PDB code: 1vzj
14757816 Y.Bourne, H.C.Kolb, Z.Radić, K.B.Sharpless, P.Taylor, and P.Marchot (2004).
Freeze-frame inhibitor captures acetylcholinesterase in a unique conformation.
  Proc Natl Acad Sci U S A, 101, 1449-1454.
PDB codes: 1q83 1q84
12761391 A.F.Mehl, L.D.Heskett, S.S.Jain, and B.Demeler (2003).
Insights into dimerization and four-helix bundle formation found by dissection of the dimer interface of the GrpE protein from Escherichia coli.
  Protein Sci, 12, 1205-1215.  
11804574 A.L.Perrier, J.Massoulié, and E.Krejci (2002).
PRiMA: the membrane anchor of acetylcholinesterase in the brain.
  Neuron, 33, 275-285.  
10890884 M.Sternfeld, S.Shoham, O.Klein, C.Flores-Flores, T.Evron, G.H.Idelson, D.Kitsberg, J.W.Patrick, and H.Soreq (2000).
Excess "read-through" acetylcholinesterase attenuates but the "synaptic" variant intensifies neurodeterioration correlates.
  Proc Natl Acad Sci U S A, 97, 8647-8652.  
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 code is shown on the right.