PDBsum entry 1puw

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Hydrolase PDB id
Jmol PyMol
Protein chain
538 a.a.
Waters ×1599
Theoretical model
PDB id:
Name: Hydrolase
Title: Theoretical model of the diisopropylphosphoryl- acetylcholinesterase complexed with 1,3-propylene-bis-n,n'- syn-4-pyridiniumaldoxime
Structure: Acetylcholinesterase. Chain: a. Synonym: ache. Ec:
Source: Homo sapiens. Human. Cell_line: hek 293. Tissue: kidney. Other_details: human embryonic kidney cells
Authors: Y.-P.Pang
Key ref:
Y.P.Pang et al. (2003). Rational design of alkylene-linked bis-pyridiniumaldoximes as improved acetylcholinesterase reactivators. Chem Biol, 10, 491-502. PubMed id: 12837382 DOI: 10.1016/S1074-5521(03)00126-1
25-Jun-03     Release date:   22-Jul-03    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P22303  (ACES_HUMAN) -  Acetylcholinesterase
614 a.a.
538 a.a.
Key:    PfamA domain  Secondary structure

 Enzyme reactions 
   Enzyme class: E.C.  - Acetylcholinesterase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Acetylcholine + H2O = choline + acetate
+ H(2)O
= choline
+ acetate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site


DOI no: 10.1016/S1074-5521(03)00126-1 Chem Biol 10:491-502 (2003)
PubMed id: 12837382  
Rational design of alkylene-linked bis-pyridiniumaldoximes as improved acetylcholinesterase reactivators.
Y.P.Pang, T.M.Kollmeyer, F.Hong, J.C.Lee, P.I.Hammond, S.P.Haugabouk, S.Brimijoin.
To improve the potency of 2-pralidoxime (2-PAM) for treating organophosphate poisoning, we dimerized 2-PAM and its analogs according to Wilson's pioneering work and the 3D structure of human acetylcholinesterase (hAChE) inactivated by isoflurophate. 1,7-Heptylene-bis-N,N'-syn-2-pyridiniumaldoxime, the most potent of the alkylene-linked dimeric reactivators, was readily synthesized using bistriflate and is 100 times more potent than 2-PAM in reactivating hAChE poisoned by isoflurophate. Experimental and computational studies confirm that 2-PAM in its biologically active form adopts the syn-I configuration. Further, they suggest that the improved performance of dimeric oximes is conferred by two-site binding with one oxime pointing toward the diisopropyl ester at the catalytic site of hAChE and the other anchored at the peripheral site. This type of binding may induce a conformational change in the acyl pocket loop which modulates the catalytic site via a domino effect.
  Selected figure(s)  
Figure 2.
Figure 2. The Reactivation Mechanism and the Design and Synthesis of Dimeric Oximes
Figure 5.
Figure 5. Close-Up Views of the Binding of 1b and 3f in Diisopropylphosphoryl-hAChEThe top shows binding with 3f, the middle shows binding with 1b, and the bottom shows an overlay of the two complexes demonstrating that the diisopropyl ester is lifted in the 1b complex.
  The above figures are reprinted by permission from Cell Press: Chem Biol (2003, 10, 491-502) copyright 2003.  
  Figures were selected by the author.  
    Author's comment    
  Related references:
1. Cholinesterase Reactivation in Vivo with a Novel Bis-Oxime Optimized by Computer-Aided Design. PI Hammond, C. Kern, F. Hong, TM Kollmeyer, Y-P Pang, and S Brimijoin, J. Pharmaco. Exp. Ther., 307, 190-196 (2003). [PubMed id: 12893843]
2. Crystal Structures of Acetylcholinesterase in Complex with HI-6, Ortho-7 and Obidoxime: Structural Basis for Differences in the Ability to Reactivate Tabun Conjugates. Fredrik Ekström, Yuan-Ping Pang, Malin Boman, Elisabet Artursson, Christine Akfur, and Susanne Lundberg, Biochemical Pharmacology, 72, 597-607, (2006). [PubMed id: 16876764]

Related structures:
2gyu - crystal structure of mus musculus acetylcholinesterase in complex with hi-6
2gyv - crystal structure of mus musculus acetylcholinesterase in complex with ortho-7
2gyw - crystal structure of mus musculus acetylcholinesterase in complex with obidoxime


Literature references that cite this PDB file's key reference

  PubMed id Reference
  20807085 F.Worek, N.Aurbek, T.Wille, P.Eyer, and H.Thiermann (2011).
Kinetic prerequisites of oximes as effective reactivators of organophosphate-inhibited acetylcholinesterase: a theoretical approach.
  J Enzyme Inhib Med Chem, 26, 303-308.  
20631426 K.Gholivand, H.Mostaanzadeh, T.Koval, M.Dusek, M.F.Erben, H.Stoeckli-Evans, and C.O.Della Védova (2010).
Syntheses, spectroscopic study and X-ray crystallography of some new phosphoramidates and lanthanide(III) complexes of N-(4-nitrobenzoyl)-N',N''-bis(morpholino)phosphoric triamide.
  Acta Crystallogr B, 66, 441-450.  
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
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.  
18369602 K.Musilek, J.Jampilek, J.Dohnal, D.Jun, F.Gunn-Moore, M.Dolezal, and K.Kuca (2008).
RP-HPLC determination of the lipophilicity of bispyridinium reactivators of acetylcholinesterase bearing a but-2-ene connecting linker.
  Anal Bioanal Chem, 391, 367-372.  
18501885 M.Calić, A.Bosak, K.Kuca, and Z.Kovarik (2008).
Interactions of butane, but-2-ene or xylene-like linked bispyridinium para-aldoximes with native and tabun-inhibited human cholinesterases.
  Chem Biol Interact, 175, 305-308.  
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
17685413 J.Kassa, J.Karasova, and L.Vasina (2007).
The evaluation of neuroprotective efficacy of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI-6) in cyclosarin-poisoned rats.
  J Appl Toxicol, 27, 621-630.  
  17449453 K.Kuca, J.Cabal, D.Jun, and K.Musilek (2007).
In vitro reactivation potency of acetylcholinesterase reactivators--K074 and K075--to reactivate tabun-inhibited human brain cholinesterases.
  Neurotox Res, 11, 101-106.  
17562604 Z.Kovarik, M.Calić, G.Sinko, and A.Bosak (2007).
Structure-activity approach in the reactivation of tabun-phosphorylated human acetylcholinesterase with bispyridinium para-aldoximes.
  Arh Hig Rada Toksikol, 58, 201-209.  
16458011 I.Merino, J.D.Thompson, C.B.Millard, J.J.Schmidt, and Y.P.Pang (2006).
Bis-imidazoles as molecular probes for peripheral sites of the zinc endopeptidase of botulinum neurotoxin serotype A.
  Bioorg Med Chem, 14, 3583-3591.  
16623863 K.Kuca, D.Jun, J.Cabal, M.Hrabinova, L.Bartosova, and V.Opletalova (2006).
Russian VX: inhibition and reactivation of acetylcholinesterase compared with VX agent.
  Basic Clin Pharmacol Toxicol, 98, 389-394.  
  18072133 K.Kuca, and D.Jun (2006).
Reactivation of sarin-inhibited pig brain acetylcholinesterase using oxime antidotes.
  J Med Toxicol, 2, 141-146.  
16092078 K.Kuca, J.Cabal, K.Musilek, D.Jun, and J.Bajgar (2005).
Effective bisquaternary reactivators of tabun-inhibited AChE.
  J Appl Toxicol, 25, 491-495.  
  15639788 K.Kuca, J.Patocka, J.Cabal, and D.Jun (2004).
Reactivation of organophosphate-inhibited acetylcholinesterase by quaternary pyridinium aldoximes.
  Neurotox Res, 6, 565-570.  
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.