PDBsum entry 1e66

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protein ligands links
Hydrolase PDB id
Protein chain
532 a.a. *
NAG ×2
Waters ×497
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Structure of acetylcholinesterase complexed with (-)-huprine x at 2.1a resolution
Structure: Acetylcholinesterase. Chain: a. Synonym: ache. Other_details: synthetic hybrid, huprine x, bound at the bottom of the active site gorge
Source: Torpedo californica. Pacific electric ray. Organism_taxid: 7787. Variant: g2 form. Organ: electric organ. Tissue: electroplaque
2.10Å     R-factor:   0.177     R-free:   0.205
Authors: H.Dvir,M.Harel,I.Silman,J.L.Sussman
Key ref:
H.Dvir et al. (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. PubMed id: 11863435 DOI: 10.1021/bi011652i
08-Aug-00     Release date:   02-Aug-01    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P04058  (ACES_TORCA) -  Acetylcholinesterase
586 a.a.
532 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     hydrolase activity     3 terms  


DOI no: 10.1021/bi011652i Biochemistry 41:2970-2981 (2002)
PubMed id: 11863435  
3D structure of Torpedo californica acetylcholinesterase complexed with huprine X at 2.1 A resolution: kinetic and molecular dynamic correlates.
H.Dvir, D.M.Wong, M.Harel, X.Barril, M.Orozco, F.J.Luque, D.Muñoz-Torrero, P.Camps, T.L.Rosenberry, I.Silman, J.L.Sussman.
Huprine X is a novel acetylcholinesterase (AChE) inhibitor, with one of the highest affinities reported for a reversible inhibitor. It is a synthetic hybrid that contains the 4-aminoquinoline substructure of one anti-Alzheimer drug, tacrine, and a carbobicyclic moiety resembling that of another AChE inhibitor, (-)-huperzine A. Cocrystallization of huprine X with Torpedo californica AChE yielded crystals whose 3D structure was determined to 2.1 A resolution. The inhibitor binds to the anionic site and also hinders access to the esteratic site. Its aromatic portion occupies the same binding site as tacrine, stacking between the aromatic rings of Trp84 and Phe330, whereas the carbobicyclic unit occupies the same binding pocket as (-)-huperzine A. Its chlorine substituent was found to lie in a hydrophobic pocket interacting with rings of the aromatic residues Trp432 and Phe330 and with the methyl groups of Met436 and Ile439. Steady-state inhibition data show that huprine X binds to human AChE and Torpedo AChE 28- and 54-fold, respectively, more tightly than tacrine. This difference stems from the fact that the aminoquinoline moiety of huprine X makes interactions similar to those made by tacrine, but additional bonds to the enzyme are made by the huperzine-like substructure and the chlorine atom. Furthermore, both tacrine and huprine X bind more tightly to Torpedo than to human AChE, suggesting that their quinoline substructures interact better with Phe330 than with Tyr337, the corresponding residue in the human AChE structure. Both (-)-huperzine A and huprine X display slow binding properties, but only binding of the former causes a peptide flip of Gly117.

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21344648 C.Ronco, R.Foucault, E.Gillon, P.Bohn, F.Nachon, L.Jean, and P.Y.Renard (2011).
New huprine derivatives functionalized at position 9 as highly potent acetylcholinesterase inhibitors.
  ChemMedChem, 6, 876-888.  
21216144 Z.F.Al-Rashid, and R.P.Hsung (2011).
(+)-Arisugacin A--computational evidence of a dual binding site covalent inhibitor of acetylcholinesterase.
  Bioorg Med Chem Lett, 21, 2687-2691.  
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.  
20347302 S.Young, K.Fabio, C.Guillon, P.Mohanta, T.A.Halton, D.E.Heck, R.A.Flowers, J.D.Laskin, and N.D.Heindel (2010).
Peripheral site acetylcholinesterase inhibitors targeting both inflammation and cholinergic dysfunction.
  Bioorg Med Chem Lett, 20, 2987-2990.  
19152365 F.Fontaine, S.Cross, G.Plasencia, M.Pastor, and I.Zamora (2009).
SHOP: a method for structure-based fragment and scaffold hopping.
  ChemMedChem, 4, 427-439.  
19816553 N.Okimoto, N.Futatsugi, H.Fuji, A.Suenaga, G.Morimoto, R.Yanai, Y.Ohno, T.Narumi, and M.Taiji (2009).
High-performance drug discovery: computational screening by combining docking and molecular dynamics simulations.
  PLoS Comput Biol, 5, e1000528.  
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.  
18464976 I.Soteras, M.Orozco, and F.J.Luque (2008).
Induction effects in metal cation-benzene complexes.
  Phys Chem Chem Phys, 10, 2616-2624.  
18273558 T.A.Pham, and A.N.Jain (2008).
Customizing scoring functions for docking.
  J Comput Aided Mol Des, 22, 269-286.  
17932031 S.Bhowmik, G.P.Horsman, J.T.Bolin, and L.D.Eltis (2007).
The molecular basis for inhibition of BphD, a C-C bond hydrolase involved in polychlorinated biphenyls degradation: large 3-substituents prevent tautomerization.
  J Biol Chem, 282, 36377-36385.
PDB codes: 2rht 2rhw
17105484 M.Fernández, and J.Caballero (2006).
Ensembles of Bayesian-regularized genetic neural networks for modeling of acetylcholinesterase inhibition by huprines.
  Chem Biol Drug Des, 68, 201-212.  
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.  
16570913 W.Luo, Q.S.Yu, S.S.Kulkarni, D.A.Parrish, H.W.Holloway, D.Tweedie, A.Shafferman, D.K.Lahiri, A.Brossi, and N.H.Greig (2006).
Inhibition of human acetyl- and butyrylcholinesterase by novel carbamates of (-)- and (+)-tetrahydrofurobenzofuran and methanobenzodioxepine.
  J Med Chem, 49, 2174-2185.  
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.  
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.  
16113998 Y.Umezawa, and M.Nishio (2005).
CH/pi hydrogen bonds as evidenced in the substrate specificity of acetylcholine esterase.
  Biopolymers, 79, 248-258.  
12725862 S.Bencharit, C.L.Morton, J.L.Hyatt, P.Kuhn, M.K.Danks, P.M.Potter, and M.R.Redinbo (2003).
Crystal structure of human carboxylesterase 1 complexed with the Alzheimer's drug tacrine: from binding promiscuity to selective inhibition.
  Chem Biol, 10, 341-349.
PDB code: 1mx1
12601798 T.Zeev-Ben-Mordehai, I.Silman, and J.L.Sussman (2003).
Acetylcholinesterase in motion: visualizing conformational changes in crystal structures by a morphing procedure.
  Biopolymers, 68, 395-406.  
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.