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PDBsum entry 1vot

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protein ligands links
Hydrolase PDB id
1vot
Jmol
Contents
Protein chain
529 a.a. *
Ligands
HUP
Waters ×208
* Residue conservation analysis
PDB id:
1vot
Name: Hydrolase
Title: Acetylcholinesterase (E.C. 3.1.1.7) complexed with huperzine
Structure: Acetylcholinesterase. Chain: a. Other_details: inter-monomer disulfide bridge
Source: Torpedo californica. Pacific electric ray. Organism_taxid: 7787. Variant: g2 form. Organ: electric organ. Tissue: electroplaque
Biol. unit: Dimer (from PDB file)
Resolution:
2.50Å     R-factor:   0.205     R-free:   0.248
Authors: M.L.Raves,M.Harel,I.Silman,J.L.Sussman
Key ref: M.L.Raves et al. (1997). Structure of acetylcholinesterase complexed with the nootropic alkaloid, (-)-huperzine A. Nat Struct Biol, 4, 57-63. PubMed id: 8989325
Date:
23-Jun-96     Release date:   16-Jun-97    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P04058  (ACES_TORCA) -  Acetylcholinesterase
Seq:
Struc:
 
Seq:
Struc:
586 a.a.
529 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
+ 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  

 

 
    reference    
 
 
Nat Struct Biol 4:57-63 (1997)
PubMed id: 8989325  
 
 
Structure of acetylcholinesterase complexed with the nootropic alkaloid, (-)-huperzine A.
M.L.Raves, M.Harel, Y.P.Pang, I.Silman, A.P.Kozikowski, J.L.Sussman.
 
  ABSTRACT  
 
(-)-Huperzine A (HupA) is found in an extract from a club moss that has been used for centuries in Chinese folk medicine. Its action has been attributed to its ability to strongly inhibit acetylcholinesterase (AChE). The crystal structure of the complex of AChE with optically pure HupA at 2.5 A resolution shows an unexpected orientation for the inhibitor with surprisingly few strong direct interactions with protein residues to explain its high affinity. This structure is compared to the native structure of AChE devoid of any inhibitor as determined to the same resolution. An analysis of the affinities of structural analogues of HupA, correlated with their interactions with the protein, shows the importance of individual hydrophobic interactions between HupA and aromatic residues in the active-site gorge of AChE.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20851778 N.Kitisripanya, P.Saparpakorn, P.Wolschann, and S.Hannongbua (2011).
Binding of huperzine A and galanthamine to acetylcholinesterase, based on ONIOM method.
  Nanomedicine, 7, 60-68.  
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.  
19536291 F.Ekström, A.Hörnberg, E.Artursson, L.G.Hammarström, G.Schneider, and Y.P.Pang (2009).
Structure of HI-6*sarin-acetylcholinesterase determined by X-ray crystallography and molecular dynamics simulation: reactivator mechanism and design.
  PLoS One, 4, e5957.
PDB codes: 2whp 2whq 2whr
19435302 M.Mihailescu, and H.Meirovitch (2009).
Absolute free energy and entropy of a mobile loop of the enzyme acetylcholinesterase.
  J Phys Chem B, 113, 7950-7964.  
19741148 Y.Aracava, E.F.Pereira, M.Akkerman, M.Adler, and E.X.Albuquerque (2009).
Effectiveness of donepezil, rivastigmine, and (+/-)huperzine A in counteracting the acute toxicity of organophosphorus nerve agents: comparison with galantamine.
  J Pharmacol Exp Ther, 331, 1014-1024.  
19714254 Y.P.Pang, F.Ekström, G.A.Polsinelli, Y.Gao, S.Rana, D.H.Hua, B.Andersson, P.O.Andersson, L.Peng, S.K.Singh, R.K.Mishra, K.Y.Zhu, A.M.Fallon, D.W.Ragsdale, and S.Brimijoin (2009).
Selective and irreversible inhibitors of mosquito acetylcholinesterases for controlling malaria and other mosquito-borne diseases.
  PLoS One, 4, e6851.
PDB code: 2wls
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.  
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.  
18588864 B.R.Coleman, R.H.Ratcliffe, S.A.Oguntayo, X.Shi, B.P.Doctor, R.K.Gordon, and M.P.Nambiar (2008).
[+]-Huperzine A treatment protects against N-methyl-D-aspartate-induced seizure/status epilepticus in rats.
  Chem Biol Interact, 175, 387-395.  
18565502 H.Y.Zhang, C.Y.Zheng, H.Yan, Z.F.Wang, L.L.Tang, X.Gao, and X.C.Tang (2008).
Potential therapeutic targets of huperzine A for Alzheimer's disease and vascular dementia.
  Chem Biol Interact, 175, 396-402.  
17657601 H.Y.Zhang, H.Yan, and X.C.Tang (2008).
Non-cholinergic effects of huperzine A: beyond inhibition of acetylcholinesterase.
  Cell Mol Neurobiol, 28, 173-183.  
18230054 J.T.Little, S.Walsh, and P.S.Aisen (2008).
An update on huperzine A as a treatment for Alzheimer's disease.
  Expert Opin Investig Drugs, 17, 209-215.  
17989799 C.Ruan, Z.Yang, and M.T.Rodgers (2007).
Influence of the d orbital occupation on the nature and strength of copper cation-pi interactions: threshold collision-induced dissociation and theoretical studies.
  Phys Chem Chem Phys, 9, 5902-5918.  
17443135 F.J.Ekström, C.Astot, and Y.P.Pang (2007).
Novel nerve-agent antidote design based on crystallographic and mass spectrometric analyses of tabun-conjugated acetylcholinesterase in complex with antidotes.
  Clin Pharmacol Ther, 82, 282-293.
PDB codes: 2jey 2jez 2jf0
18033585 J.Stöckigt, and S.Panjikar (2007).
Structural biology in plant natural product biosynthesis--architecture of enzymes from monoterpenoid indole and tropane alkaloid biosynthesis.
  Nat Prod Rep, 24, 1382-1400.  
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.  
17565384 Q.Wang, and Y.P.Pang (2007).
Accurate reproduction of 161 small-molecule complex crystal structures using the EUDOC program: expanding the use of EUDOC to supramolecular chemistry.
  PLoS ONE, 2, e531.  
17879332 S.Rana, B.Kundu, and S.Durani (2007).
A mixed-alpha,beta miniprotein stereochemically reprogrammed to high-binding affinity for acetylcholine.
  Biopolymers, 87, 231-243.  
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.  
17021015 J.M.Bui, and J.A.McCammon (2006).
Protein complex formation by acetylcholinesterase and the neurotoxin fasciculin-2 appears to involve an induced-fit mechanism.
  Proc Natl Acad Sci U S A, 103, 15451-15456.  
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.  
16364207 R.Wang, H.Yan, and X.C.Tang (2006).
Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine.
  Acta Pharmacol Sin, 27, 1.  
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
17183688 Y.P.Pang (2006).
Novel acetylcholinesterase target site for malaria mosquito control.
  PLoS ONE, 1, e58.  
16923332 Y.Q.Liang, and X.C.Tang (2006).
Comparative studies of huperzine A, donepezil, and rivastigmine on brain acetylcholine, dopamine, norepinephrine, and 5-hydroxytryptamine levels in freely-moving rats.
  Acta Pharmacol Sin, 27, 1127-1136.  
15739192 T.K.Manojkumar, C.Cui, and K.S.Kim (2005).
Theoretical insights into the mechanism of acetylcholinesterase-catalyzed acylation of acetylcholine.
  J Comput Chem, 26, 606-611.  
16113998 Y.Umezawa, and M.Nishio (2005).
CH/pi hydrogen bonds as evidenced in the substrate specificity of acetylcholine esterase.
  Biopolymers, 79, 248-258.  
15162493 A.Berchanski, B.Shapira, and M.Eisenstein (2004).
Hydrophobic complementarity in protein-protein docking.
  Proteins, 56, 130-142.  
15111430 M.Weik, X.Vernede, A.Royant, and D.Bourgeois (2004).
Temperature derivative fluorescence spectroscopy as a tool to study dynamical changes in protein crystals.
  Biophys J, 86, 3176-3185.  
15604663 S.P.Fletcher, B.C.Geyer, A.Smith, T.Evron, L.Joshi, H.Soreq, and T.S.Mor (2004).
Tissue distribution of cholinesterases and anticholinesterases in native and transgenic tomato plants.
  Plant Mol Biol, 55, 33-43.  
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.  
12784363 E.Ben-Zeev, and M.Eisenstein (2003).
Weighted geometric docking: incorporating external information in the rotation-translation scan.
  Proteins, 52, 24-27.  
12851386 J.L.Johnson, B.Cusack, T.F.Hughes, E.H.McCullough, A.Fauq, P.Romanovskis, A.F.Spatola, and T.L.Rosenberry (2003).
Inhibitors tethered near the acetylcholinesterase active site serve as molecular rulers of the peripheral and acylation sites.
  J Biol Chem, 278, 38948-38955.  
12759360 J.Shi, K.Tai, J.A.McCammon, P.Taylor, and D.A.Johnson (2003).
Nanosecond dynamics of the mouse acetylcholinesterase cys69-cys96 omega loop.
  J Biol Chem, 278, 30905-30911.  
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
11847280 A.Heifetz, E.Katchalski-Katzir, and M.Eisenstein (2002).
Electrostatics in protein-protein docking.
  Protein Sci, 11, 571-587.  
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.  
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
12196517 J.Shi, Z.Radic', and P.Taylor (2002).
Inhibitors of different structure induce distinguishing conformations in the omega loop, Cys69-Cys96, of mouse acetylcholinesterase.
  J Biol Chem, 277, 43301-43308.  
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.  
11567086 M.Weik, R.B.Ravelli, I.Silman, J.L.Sussman, P.Gros, and J.Kroon (2001).
Specific protein dynamics near the solvent glass transition assayed by radiation-induced structural changes.
  Protein Sci, 10, 1953-1961.  
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.  
  10739260 I.Tsigelny, I.N.Shindyalov, P.E.Bourne, T.C.Südhof, and P.Taylor (2000).
Common EF-hand motifs in cholinesterases and neuroligins suggest a role for Ca2+ binding in cell surface associations.
  Protein Sci, 9, 180-185.  
10609549 J.Chang (2000).
Medicinal herbs: drugs or dietary supplements?
  Biochem Pharmacol, 59, 211-219.  
  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
10639129 M.Weik, R.B.Ravelli, G.Kryger, S.McSweeney, M.L.Raves, M.Harel, P.Gros, I.Silman, J.Kroon, and J.L.Sussman (2000).
Specific chemical and structural damage to proteins produced by synchrotron radiation.
  Proc Natl Acad Sci U S A, 97, 623-628.
PDB codes: 1qid 1qie 1qif 1qig 1qih 1qii 1qij 1qik 1qim 1qio
10745008 R.B.Ravelli, and S.M.McSweeney (2000).
The 'fingerprint' that X-rays can leave on structures.
  Structure, 8, 315-328.  
10074358 A.Ordentlich, D.Barak, C.Kronman, H.P.Benschop, L.P.De Jong, N.Ariel, R.Barak, Y.Segall, B.Velan, and A.Shafferman (1999).
Exploring the active center of human acetylcholinesterase with stereomers of an organophosphorus inhibitor with two chiral centers.
  Biochemistry, 38, 3055-3066.  
10353814 C.B.Millard, G.Kryger, A.Ordentlich, H.M.Greenblatt, M.Harel, M.L.Raves, Y.Segall, D.Barak, A.Shafferman, I.Silman, and J.L.Sussman (1999).
Crystal structures of aged phosphonylated acetylcholinesterase: nerve agent reaction products at the atomic level.
  Biochemistry, 38, 7032-7039.
PDB codes: 1cfj 1som 2dfp
10231521 C.Bartolucci, E.Perola, L.Cellai, M.Brufani, and D.Lamba (1999).
"Back door" opening implied by the crystal structure of a carbamoylated acetylcholinesterase.
  Biochemistry, 38, 5714-5719.
PDB code: 1oce
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.  
10368299 G.Kryger, I.Silman, and J.L.Sussman (1999).
Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs.
  Structure, 7, 297-307.
PDB code: 1eve
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.  
10404588 P.Heikinheimo, A.Goldman, C.Jeffries, and D.L.Ollis (1999).
Of barn owls and bankers: a lush variety of alpha/beta hydrolases.
  Structure, 7, R141-R146.  
10341665 S.Tara, T.P.Straatsma, and J.A.McCammon (1999).
Mouse acetylcholinesterase unliganded and in complex with huperzine A: a comparison of molecular dynamics simulations.
  Biopolymers, 50, 35-43.  
10423544 S.Tara, V.Helms, T.P.Straatsma, and J.A.McCammon (1999).
Molecular dynamics of mouse acetylcholinesterase complexed with huperzine A.
  Biopolymers, 50, 347-359.  
9915834 Y.Bourne, P.Taylor, P.E.Bougis, and P.Marchot (1999).
Crystal structure of mouse acetylcholinesterase. A peripheral site-occluding loop in a tetrameric assembly.
  J Biol Chem, 274, 2963-2970.
PDB code: 1maa
9677373 A.Ordentlich, D.Barak, C.Kronman, N.Ariel, Y.Segall, B.Velan, and A.Shafferman (1998).
Functional characteristics of the oxyanion hole in human acetylcholinesterase.
  J Biol Chem, 273, 19509-19517.  
9873409 F.Zeng, H.Jiang, X.Tang, K.Chen, and R.Ji (1998).
Synthesis and acetylcholinesterase inhibitory activity of (+/-)-14-fluorohuperzine A.
  Bioorg Med Chem Lett, 8, 1661-1664.  
9631300 J.A.McCammon (1998).
Theory of biomolecular recognition.
  Curr Opin Struct Biol, 8, 245-249.  
9548741 J.C.Chen, L.J.Miercke, J.Krucinski, J.R.Starr, G.Saenz, X.Wang, C.A.Spilburg, L.G.Lange, J.L.Ellsworth, and R.M.Stroud (1998).
Structure of bovine pancreatic cholesterol esterase at 1.6 A: novel structural features involved in lipase activation.
  Biochemistry, 37, 5107-5117.
PDB code: 2bce
9860822 L.McFail-Isom, X.Shui, and L.D.Williams (1998).
Divalent cations stabilize unstacked conformations of DNA and RNA by interacting with base pi systems.
  Biochemistry, 37, 17105-17111.  
9692976 P.T.Williamson, G.Gröbner, P.J.Spooner, K.W.Miller, and A.Watts (1998).
Probing the agonist binding pocket in the nicotinic acetylcholine receptor: a high-resolution solid-state NMR approach.
  Biochemistry, 37, 10854-10859.  
9521743 T.Szegletes, W.D.Mallender, and T.L.Rosenberry (1998).
Nonequilibrium analysis alters the mechanistic interpretation of inhibition of acetylcholinesterase by peripheral site ligands.
  Biochemistry, 37, 4206-4216.  
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.