PDBsum entry 1eve

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Serine hydrolase PDB id
Protein chain
534 a.a. *
NAG ×3
Waters ×396
* Residue conservation analysis
PDB id:
Name: Serine hydrolase
Title: Three dimensional structure of the anti-alzheimer drug, e202 (aricept), complexed with its target acetylcholinesterase
Structure: Acetylcholinesterase. Chain: a. Ec:
Source: Torpedo californica. Pacific electric ray. Organism_taxid: 7787. Variant: g2 form. Organ: electric organ. Tissue: electroplaque
2.50Å     R-factor:   0.188     R-free:   0.228
Authors: G.Kryger,I.Silman,J.L.Sussman
Key ref:
G.Kryger et al. (1999). Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs. Structure, 7, 297-307. PubMed id: 10368299 DOI: 10.1016/S0969-2126(99)80040-9
04-Mar-98     Release date:   20-Jan-99    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P04058  (ACES_TORCA) -  Acetylcholinesterase
586 a.a.
534 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Acetylcholinesterase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Acetylcholine + H2O = choline + acetate
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     synapse   5 terms 
  Biological process     neurotransmitter catabolic process   2 terms 
  Biochemical function     carboxylic ester hydrolase activity     4 terms  


DOI no: 10.1016/S0969-2126(99)80040-9 Structure 7:297-307 (1999)
PubMed id: 10368299  
Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs.
G.Kryger, I.Silman, J.L.Sussman.
BACKGROUND: Several cholinesterase inhibitors are either being utilized for symptomatic treatment of Alzheimer's disease or are in advanced clinical trials. E2020, marketed as Aricept, is a member of a large family of N-benzylpiperidine-based acetylcholinesterase (AChE) inhibitors developed, synthesized and evaluated by the Eisai Company in Japan. These inhibitors were designed on the basis of QSAR studies, prior to elucidation of the three-dimensional structure of Torpedo californica AChE (TcAChE). It significantly enhances performance in animal models of cholinergic hypofunction and has a high affinity for AChE, binding to both electric eel and mouse AChE in the nanomolar range. RESULTS: Our experimental structure of the E2020-TcAChE complex pinpoints specific interactions responsible for the high affinity and selectivity demonstrated previously. It shows that E2020 has a unique orientation along the active-site gorge, extending from the anionic subsite of the active site, at the bottom, to the peripheral anionic site, at the top, via aromatic stacking interactions with conserved aromatic acid residues. E2020 does not, however, interact directly with either the catalytic triad or the 'oxyanion hole', but only indirectly via solvent molecules. CONCLUSIONS: Our study shows, a posteriori, that the design of E2020 took advantage of several important features of the active-site gorge of AChE to produce a drug with both high affinity for AChE and a high degree of selectivity for AChE versus butyrylcholinesterase (BChE). It also delineates voids within the gorge that are not occupied by E2020 and could provide sites for potential modification of E2020 to produce drugs with improved pharmacological profiles.
  Selected figure(s)  
Figure 3.
  The above figure is reprinted by permission from Cell Press: Structure (1999, 7, 297-307) copyright 1999.  
  Figure was selected by an automated process.  

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.
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21541844 K.Ramanathan, V.Shanthi, and R.Sethumadhavan (2011).
A compact review on the comparison of conventional and non-conventional interactions on the structural stability of therapeutic proteins.
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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.  
21216144 Z.F.Al-Rashid, and R.P.Hsung (2011).
(+)-Arisugacin A--computational evidence of a dual binding site covalent inhibitor of acetylcholinesterase.
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20345171 C.Bissantz, B.Kuhn, and M.Stahl (2010).
A medicinal chemist's guide to molecular interactions.
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20859987 E.Viayna, T.Gómez, C.Galdeano, L.Ramírez, M.Ratia, A.Badia, M.V.Clos, E.Verdaguer, F.Junyent, A.Camins, M.Pallàs, M.Bartolini, F.Mancini, V.Andrisano, M.P.Arce, M.I.Rodríguez-Franco, A.Bidon-Chanal, F.J.Luque, P.Camps, and D.Muñoz-Torrero (2010).
Novel huprine derivatives with inhibitory activity toward β-amyloid aggregation and formation as disease-modifying anti-alzheimer drug candidates.
  ChemMedChem, 5, 1855-1870.  
20190429 N.Toda, T.Kaneko, and H.Kogen (2010).
Development of an efficient therapeutic agent for Alzheimer's disease: design and synthesis of dual inhibitors of acetylcholinesterase and serotonin transporter.
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21052939 Z.Jin, L.Yang, S.J.Liu, J.Wang, S.Li, H.Q.Lin, D.C.Wan, and C.Hu (2010).
Synthesis and biological evaluation of 3,6-diaryl-7H-thiazolo[3,2-b] [1,2,4]triazin-7-one derivatives as acetylcholinesterase inhibitors.
  Arch Pharm Res, 33, 1641-1649.  
18729824 D.Barak, A.Ordentlich, D.Stein, Q.S.Yu, N.H.Greig, and A.Shafferman (2009).
Accommodation of physostigmine and its analogues by acetylcholinesterase is dominated by hydrophobic interactions.
  Biochem J, 417, 213-222.  
19263097 F.Fan, Z.You, Z.Li, J.Cheng, Y.Tang, and Z.Tang (2009).
A butterfly effect: highly insecticidal resistance caused by only a conservative residue mutated of drosophila melanogaster acetylcholinesterase.
  J Mol Model, 15, 1229-1236.  
19460190 J.M.Miezan Ezoulin, B.Y.Shao, Z.Xia, Q.Xie, J.Li, Y.Y.Cui, H.Wang, C.Z.Dong, Y.X.Zhao, F.Massicot, Z.B.Qiu, F.Heymans, and H.Z.Chen (2009).
Novel piperazine derivative PMS1339 exhibits tri-functional properties and cognitive improvement in mice.
  Int J Neuropsychopharmacol, 12, 1409-1419.  
19889539 K.A.Rawls, P.T.Lang, J.Takeuchi, S.Imamura, T.D.Baguley, C.Grundner, T.Alber, and J.A.Ellman (2009).
Fragment-based discovery of selective inhibitors of the Mycobacterium tuberculosis protein tyrosine phosphatase PtpA.
  Bioorg Med Chem Lett, 19, 6851-6854.  
19308922 M.I.Fernández-Bachiller, C.Pérez, N.E.Campillo, J.A.Páez, G.C.González-Muñoz, P.Usán, E.García-Palomero, M.G.López, M.Villarroya, A.G.García, A.Martínez, and M.I.Rodríguez-Franco (2009).
Tacrine-melatonin hybrids as multifunctional agents for Alzheimer's disease, with cholinergic, antioxidant, and neuroprotective properties.
  ChemMedChem, 4, 828-841.  
19292865 M.Pietsch, L.Christian, T.Inhester, S.Petzold, and M.Gütschow (2009).
Kinetics of inhibition of acetylcholinesterase in the presence of acetonitrile.
  FEBS J, 276, 2292-2307.  
18941902 R.Gil-Redondo, J.Estrada, A.Morreale, F.Herranz, J.Sancho, and A.R.Ortiz (2009).
VSDMIP: virtual screening data management on an integrated platform.
  J Comput Aided Mol Des, 23, 171-184.  
18434503 Y.N.Imai, Y.Inoue, I.Nakanishi, and K.Kitaura (2008).
Cl-pi interactions in protein-ligand complexes.
  Protein Sci, 17, 1129-1137.  
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.  
17191291 A.Di Fenza, A.Heine, U.Koert, and G.Klebe (2007).
Understanding Binding Selectivity toward Trypsin and Factor Xa: the Role of Aromatic Interactions.
  ChemMedChem, 2, 297-308.
PDB codes: 1y59 1y5a 1y5b 1y5u
17448663 E.Hodis, G.Schreiber, K.Rother, and J.L.Sussman (2007).
eMovie: a storyboard-based tool for making molecular movies.
  Trends Biochem Sci, 32, 199-204.  
17279501 H.Yuki, Y.Tanaka, M.Hata, H.Ishikawa, S.Neya, and T.Hoshino (2007).
Implementation of pi-pi interactions in molecular dynamics simulation.
  J Comput Chem, 28, 1091-1099.  
18031622 L.L.Shen, G.X.Liu, and Y.Tang (2007).
Molecular docking and 3D-QSAR studies of 2-substituted 1-indanone derivatives as acetylcholinesterase inhibitors.
  Acta Pharmacol Sin, 28, 2053-2063.  
17148911 K.Ravikumar, B.Sridhar, D.G.Sathe, A.V.Naidu, and K.D.Sawant (2006).
Donepezilium oxalate trihydrate, a therapeutic agent for Alzheimer's disease.
  Acta Crystallogr C, 62, o681-o683.  
16341717 L.Alisaraie, and G.Fels (2006).
Molecular docking study on the "back door" hypothesis for product clearance in acetylcholinesterase.
  J Mol Model, 12, 348-354.  
16404617 Q.Xie, Y.Tang, W.Li, X.H.Wang, and Z.B.Qiu (2006).
Investigation of the binding mode of (-)-meptazinol and bis-meptazinol derivatives on acetylcholinesterase using a molecular docking method.
  J Mol Model, 12, 390-397.  
16835922 S.Chakkaravarthi, M.M.Babu, M.M.Gromiha, G.Jayaraman, and R.Sethumadhavan (2006).
Exploring the environmental preference of weak interactions in (alpha/beta)8 barrel proteins.
  Proteins, 65, 75-86.  
16837465 Y.Bourne, Z.Radic, G.Sulzenbacher, E.Kim, P.Taylor, and P.Marchot (2006).
Substrate and product trafficking through the active center gorge of acetylcholinesterase analyzed by crystallography and equilibrium binding.
  J Biol Chem, 281, 29256-29267.
PDB codes: 2h9y 2ha0 2ha2 2ha3 2ha4 2ha5 2ha6 2ha7
16018582 A.D.Obregon, M.R.Schetinger, M.M.Correa, V.M.Morsch, J.E.da Silva, M.A.Martins, H.G.Bonacorso, and N.Zanatta (2005).
Effects per se of organic solvents in the cerebral acetylcholinesterase of rats.
  Neurochem Res, 30, 379-384.  
16230018 D.Alonso, I.Dorronsoro, L.Rubio, P.Muñoz, E.García-Palomero, M.Del Monte, A.Bidon-Chanal, M.Orozco, F.J.Luque, A.Castro, M.Medina, and A.Martínez (2005).
Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE.
  Bioorg Med Chem, 13, 6588-6597.  
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.  
15190239 R.M.Lane, M.Kivipelto, and N.H.Greig (2004).
Acetylcholinesterase and its inhibition in Alzheimer disease.
  Clin Neuropharmacol, 27, 141-149.  
14622273 A.Saxena, J.M.Fedorko, C.R.Vinayaka, R.Medhekar, Z.Radić, P.Taylor, O.Lockridge, and B.P.Doctor (2003).
Aromatic amino-acid residues at the active and peripheral anionic sites control the binding of E2020 (Aricept) to cholinesterases.
  Eur J Biochem, 270, 4447-4458.  
12824323 M.M.Babu (2003).
NCI: A server to identify non-canonical interactions in protein structures.
  Nucleic Acids Res, 31, 3345-3348.  
12838268 S.J.Teague (2003).
Implications of protein flexibility for drug discovery.
  Nat Rev Drug Discov, 2, 527-541.  
12351819 C.E.Felder, M.Harel, I.Silman, and J.L.Sussman (2002).
Structure of a complex of the potent and specific inhibitor BW284C51 with Torpedo californica acetylcholinesterase.
  Acta Crystallogr D Biol Crystallogr, 58, 1765-1771.
PDB code: 1e3q
11863435 H.Dvir, D.M.Wong, M.Harel, X.Barril, M.Orozco, F.J.Luque, D.Muñoz-Torrero, P.Camps, T.L.Rosenberry, I.Silman, and J.L.Sussman (2002).
3D structure of Torpedo californica acetylcholinesterase complexed with huprine X at 2.1 A resolution: kinetic and molecular dynamic correlates.
  Biochemistry, 41, 2970-2981.
PDB code: 1e66
11967565 S.Bencharit, C.L.Morton, E.L.Howard-Williams, M.K.Danks, P.M.Potter, and M.R.Redinbo (2002).
Structural insights into CPT-11 activation by mammalian carboxylesterases.
  Nat Struct Biol, 9, 337-342.
PDB code: 1k4y
11526341 A.Nicolas, F.Ferron, L.Toker, J.L.Sussman, and I.Silman (2001).
Histochemical method for characterization of enzyme crystals: application to crystals of Torpedo californica acetylcholinesterase.
  Acta Crystallogr D Biol Crystallogr, 57, 1348-1350.  
11119642 C.Bartolucci, E.Perola, C.Pilger, G.Fels, and D.Lamba (2001).
Three-dimensional structure of a complex of galanthamine (Nivalin) with acetylcholinesterase from Torpedo californica: implications for the design of new anti-Alzheimer drugs.
  Proteins, 42, 182-191.
PDB code: 1qti
12116409 Y.P.Pang, E.Perola, K.Xu, and F.G.Prendergast (2001).
EUDOC: a computer program for identification of drug interaction sites in macromolecules and drug leads from chemical databases.
  J Comput Chem, 22, 1750-1771.  
  10892800 M.Harel, G.Kryger, T.L.Rosenberry, W.D.Mallender, T.Lewis, R.J.Fletcher, J.M.Guss, I.Silman, and J.L.Sussman (2000).
Three-dimensional structures of Drosophila melanogaster acetylcholinesterase and of its complexes with two potent inhibitors.
  Protein Sci, 9, 1063-1072.
PDB codes: 1dx4 1qo9 1qon
10612585 F.Zeng, H.Jiang, Y.Zhai, H.Zhang, K.Chen, and R.Ji (1999).
Synthesis and acetylcholinesterase inhibitory activity of huperzine A-E2020 combined compound.
  Bioorg Med Chem Lett, 9, 3279-3284.  
10574966 J.W.Chen, Y.L.Luo, M.J.Hwang, F.C.Peng, and K.H.Ling (1999).
Territrem B, a tremorgenic mycotoxin that inhibits acetylcholinesterase with a noncovalent yet irreversible binding mechanism.
  J Biol Chem, 274, 34916-34923.  
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.