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PDBsum entry 1f8u

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protein ligands Protein-protein interface(s) links
Hydrolase/toxin PDB id
1f8u
Jmol
Contents
Protein chains
531 a.a. *
61 a.a. *
Ligands
NAG-NAG
Waters ×117
* Residue conservation analysis
PDB id:
1f8u
Name: Hydrolase/toxin
Title: Crystal structure of mutant e202q of human acetylcholinester complexed with green mamba venom peptide fasciculin-ii
Structure: Acetylcholinesterase. Chain: a. Engineered: yes. Fasciculin ii. Chain: b
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ache. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek 293. Expression_system_tissue: kidney. Expression_system_cell: human embryonic kidney cells.
Biol. unit: Tetramer (from PQS)
Resolution:
2.90Å     R-factor:   0.191     R-free:   0.227
Authors: G.Kryger,M.Harel,A.Shafferman,I.Silman,J.L.Sussman
Key ref:
G.Kryger et al. (2000). Structures of recombinant native and E202Q mutant human acetylcholinesterase complexed with the snake-venom toxin fasciculin-II. Acta Crystallogr D Biol Crystallogr, 56, 1385-1394. PubMed id: 11053835 DOI: 10.1107/S0907444900010659
Date:
05-Jul-00     Release date:   17-Jan-01    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P22303  (ACES_HUMAN) -  Acetylcholinesterase
Seq:
Struc:
 
Seq:
Struc:
614 a.a.
531 a.a.*
Protein chain
Pfam   ArchSchema ?
P0C1Z0  (TXFA2_DENAN) -  Fasciculin-2
Seq:
Struc:
61 a.a.
61 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chain A: 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!
  Cellular component     extracellular region   18 terms 
  Biological process     small molecule metabolic process   30 terms 
  Biochemical function     protein binding     11 terms  

 

 
    reference    
 
 
DOI no: 10.1107/S0907444900010659 Acta Crystallogr D Biol Crystallogr 56:1385-1394 (2000)
PubMed id: 11053835  
 
 
Structures of recombinant native and E202Q mutant human acetylcholinesterase complexed with the snake-venom toxin fasciculin-II.
G.Kryger, M.Harel, K.Giles, L.Toker, B.Velan, A.Lazar, C.Kronman, D.Barak, N.Ariel, A.Shafferman, I.Silman, J.L.Sussman.
 
  ABSTRACT  
 
Structures of recombinant wild-type human acetylcholinesterase and of its E202Q mutant as complexes with fasciculin-II, a 'three-finger' polypeptide toxin purified from the venom of the eastern green mamba (Dendroaspis angusticeps), are reported. The structure of the complex of the wild-type enzyme was solved to 2.8 A resolution by molecular replacement starting from the structure of the complex of Torpedo californica acetylcholinesterase with fasciculin-II and verified by starting from a similar complex with mouse acetylcholinesterase. The overall structure is surprisingly similar to that of the T. californica enzyme with fasciculin-II and, as expected, to that of the mouse acetylcholinesterase complex. The structure of the E202Q mutant complex was refined starting from the corresponding wild-type human acetylcholinesterase structure, using the 2.7 A resolution data set collected. Comparison of the two structures shows that removal of the charged group from the protein core and its substitution by a neutral isosteric moiety does not disrupt the functional architecture of the active centre. One of the elements of this architecture is thought to be a hydrogen-bond network including residues Glu202, Glu450, Tyr133 and two bridging molecules of water, which is conserved in other vertebrate acetylcholinesterases as well as in the human enzyme. The present findings are consistent with the notion that the main role of this network is the proper positioning of the Glu202 carboxylate relative to the catalytic triad, thus defining its functional role in the interaction of acetylcholinesterase with substrates and inhibitors.
 
  Selected figure(s)  
 
Figure 4.
Figure 4 Schematic comparison of packing diagrams of AChE-FAS-II complexes, looking down the z axis with the monomers of the AChE dimers shown in green and blue and FAS-II shown in red: (a) hAChE-FAS-II; (b) TcAChE-FAS-II; (c) mAChE-FAS-II.
Figure 7.
Figure 7 4.0 Å contact footprint between AChE and FAS-II. On the left, molecular surface of hAChE in yellow, with atoms [248]<= 4.0 Å from FAS-II rendered in red and atoms lining the active-site gorge rendered in grey. On the right, molecular surface of FAS-II in green, with atoms [249]<= 4.0 Å from hAChE atoms rendered in blue.
 
  The above figures are reprinted by permission from the IUCr: Acta Crystallogr D Biol Crystallogr (2000, 56, 1385-1394) copyright 2000.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21397996 F.Belluti, M.Bartolini, G.Bottegoni, A.Bisi, A.Cavalli, V.Andrisano, and A.Rampa (2011).
Benzophenone-based derivatives: a novel series of potent and selective dual inhibitors of acetylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation.
  Eur J Med Chem, 46, 1682-1693.  
21397501 M.Komloova, K.Musilek, A.Horova, O.Holas, V.Dohnal, F.Gunn-Moore, and K.Kuca (2011).
Preparation, in vitro screening and molecular modelling of symmetrical bis-quinolinium cholinesterase inhibitors--implications for early myasthenia gravis treatment.
  Bioorg Med Chem Lett, 21, 2505-2509.  
21251245 S.H.Lu, J.W.Wu, H.L.Liu, J.H.Zhao, K.T.Liu, C.K.Chuang, H.Y.Lin, W.B.Tsai, and Y.Ho (2011).
The discovery of potential acetylcholinesterase inhibitors: a combination of pharmacophore modeling, virtual screening, and molecular docking studies.
  J Biomed Sci, 18, 8.  
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.  
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.  
19603258 D.Chekmarev, V.Kholodovych, S.Kortagere, W.J.Welsh, and S.Ekins (2009).
Predicting inhibitors of acetylcholinesterase by regression and classification machine learning approaches with combinations of molecular descriptors.
  Pharm Res, 26, 2216-2224.  
19924840 J.Liu, Y.Zhang, and C.G.Zhan (2009).
Reaction pathway and free-energy barrier for reactivation of dimethylphosphoryl-inhibited human acetylcholinesterase.
  J Phys Chem B, 113, 16226-16236.  
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.  
19715346 N.H.Barakat, X.Zheng, C.B.Gilley, M.MacDonald, K.Okolotowicz, J.R.Cashman, S.Vyas, J.M.Beck, C.M.Hadad, and J.Zhang (2009).
Chemical synthesis of two series of nerve agent model compounds and their stereoselective interaction with human acetylcholinesterase and human butyrylcholinesterase.
  Chem Res Toxicol, 22, 1669-1679.  
19643977 O.Sharabi, Y.Peleg, E.Mashiach, E.Vardy, Y.Ashani, I.Silman, J.L.Sussman, and J.M.Shifman (2009).
Design, expression and characterization of mutants of fasciculin optimized for interaction with its target, acetylcholinesterase.
  Protein Eng Des Sel, 22, 641-648.  
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.  
19194505 Y.P.Pang, S.K.Singh, Y.Gao, T.L.Lassiter, R.K.Mishra, K.Y.Zhu, and S.Brimijoin (2009).
Selective and irreversible inhibitors of aphid acetylcholinesterases: steps toward human-safe insecticides.
  PLoS ONE, 4, e4349.  
18485004 A.Galat, G.Gross, P.Drevet, A.Sato, and A.Ménez (2008).
Conserved structural determinants in three-fingered protein domains.
  FEBS J, 275, 3207-3225.  
18343962 A.V.Nemukhin, S.V.Lushchekina, A.V.Bochenkova, A.A.Golubeva, and S.D.Varfolomeev (2008).
Characterization of a complete cycle of acetylcholinesterase catalysis by ab initio QM/MM modeling.
  J Mol Model, 14, 409-416.  
17729290 G.Petraglio, M.Bartolini, D.Branduardi, V.Andrisano, M.Recanatini, F.L.Gervasio, A.Cavalli, and M.Parrinello (2008).
The role of Li+, Na+, and K+ in the ligand binding inside the human acetylcholinesterase gorge.
  Proteins, 70, 779-785.  
17932038 O.Cohen, C.Kronman, A.Lazar, B.Velan, and A.Shafferman (2007).
Controlled concealment of exposed clearance and immunogenic domains by site-specific polyethylene glycol attachment to acetylcholinesterase hypolysine mutants.
  J Biol Chem, 282, 35491-35501.  
16955366 S.Darvesh, R.Walsh, and E.Martin (2007).
Homocysteine thiolactone and human cholinesterases.
  Cell Mol Neurobiol, 27, 33-48.  
16763558 J.P.Colletier, D.Fournier, H.M.Greenblatt, J.Stojan, J.L.Sussman, G.Zaccai, I.Silman, and M.Weik (2006).
Structural insights into substrate traffic and inhibition in acetylcholinesterase.
  EMBO J, 25, 2746-2756.
PDB codes: 2c4h 2c58 2c5f 2c5g
16586114 L.Pezzementi, M.Rowland, M.Wolfe, and I.Tsigelny (2006).
Inactivation of an invertebrate acetylcholinesterase by sulfhydryl reagents: the roles of two cysteines in the catalytic gorge of the enzyme.
  Invert Neurosci, 6, 47-55.  
16648374 Z.Talebizadeh, D.Y.Lam, M.F.Theodoro, D.C.Bittel, G.H.Lushington, and M.G.Butler (2006).
Novel splice isoforms for NLGN3 and NLGN4 with possible implications in autism.
  J Med Genet, 43, e21.  
16183292 M.I.Rodríguez-Franco, M.I.Fernández-Bachiller, C.Pérez, A.Castro, and A.Martínez (2005).
Design and synthesis of N-benzylpiperidine-purine derivatives as new dual inhibitors of acetyl- and butyrylcholinesterase.
  Bioorg Med Chem, 13, 6795-6802.  
15582466 S.Darvesh, R.S.McDonald, A.Penwell, S.Conrad, K.V.Darvesh, D.Mataija, G.Gomez, A.Caines, R.Walsh, and E.Martin (2005).
Structure-activity relationships for inhibition of human cholinesterases by alkyl amide phenothiazine derivatives.
  Bioorg Med Chem, 13, 211-222.  
15078872 A.E.Boyd, C.S.Dunlop, L.Wong, Z.Radic, P.Taylor, and D.A.Johnson (2004).
Nanosecond dynamics of acetylcholinesterase near the active center gorge.
  J Biol Chem, 279, 26612-26618.  
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
15030487 J.Stojan, L.Brochier, C.Alies, J.P.Colletier, and D.Fournier (2004).
Inhibition of Drosophila melanogaster acetylcholinesterase by high concentrations of substrate.
  Eur J Biochem, 271, 1364-1371.  
15459952 Y.Hasin, N.Avidan, D.Bercovich, A.Korczyn, I.Silman, J.S.Beckmann, and J.L.Sussman (2004).
A paradigm for single nucleotide polymorphism analysis: the case of the acetylcholinesterase gene.
  Hum Mutat, 24, 408-416.  
12679808 S.Bencharit, C.L.Morton, Y.Xue, P.M.Potter, and M.R.Redinbo (2003).
Structural basis of heroin and cocaine metabolism by a promiscuous human drug-processing enzyme.
  Nat Struct Biol, 10, 349-356.
PDB codes: 1mx5 1mx9
12505979 Y.Bourne, P.Taylor, Z.Radić, and P.Marchot (2003).
Structural insights into ligand interactions at the acetylcholinesterase peripheral anionic site.
  EMBO J, 22, 1.
PDB codes: 1j06 1j07 1ku6 1n5m 1n5r
12869558 Y.Nicolet, O.Lockridge, P.Masson, J.C.Fontecilla-Camps, and F.Nachon (2003).
Crystal structure of human butyrylcholinesterase and of its complexes with substrate and products.
  J Biol Chem, 278, 41141-41147.
PDB codes: 1p0i 1p0m 1p0p 1p0q
12837382 Y.P.Pang, T.M.Kollmeyer, F.Hong, J.C.Lee, P.I.Hammond, S.P.Haugabouk, and S.Brimijoin (2003).
Rational design of alkylene-linked bis-pyridiniumaldoximes as improved acetylcholinesterase reactivators.
  Chem Biol, 10, 491-502.
PDB codes: 1jga 1jgb 1puv 1puw
12199708 C.Cléry-Barraud, A.Ordentlich, H.Grosfeld, A.Shafferman, and P.Masson (2002).
Pressure and heat inactivation of recombinant human acetylcholinesterase. Importance of residue E202 for enzyme stability.
  Eur J Biochem, 269, 4297-4307.  
11856322 F.Nachon, Y.Nicolet, N.Viguié, P.Masson, J.C.Fontecilla-Camps, and O.Lockridge (2002).
Engineering of a monomeric and low-glycosylated form of human butyrylcholinesterase: expression, purification, characterization and crystallization.
  Eur J Biochem, 269, 630-637.  
11517229 J.Shi, A.E.Boyd, Z.Radic, and P.Taylor (2001).
Reversibly bound and covalently attached ligands induce conformational changes in the omega loop, Cys69-Cys96, of mouse acetylcholinesterase.
  J Biol Chem, 276, 42196-42204.  
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 codes are shown on the right.