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PDBsum entry 3dkk

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protein ligands metals links
Hydrolase PDB id
3dkk
Jmol
Contents
Protein chain
527 a.a. *
Ligands
NAG-NAG-FUL ×2
NAG-FUL
NAG ×3
SO4
Metals
_CL ×2
_NA
Waters ×254
* Residue conservation analysis
PDB id:
3dkk
Name: Hydrolase
Title: Aged form of human butyrylcholinesterase inhibited by tabun
Structure: Cholinesterase. Chain: a. Fragment: unp residues 29-557. Synonym: acylcholine acylhydrolase, choline esterase ii, butyrylcholine esterase, pseudocholinesterase. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Cell_line: ovary cells. Gene: bche, che1. Expressed in: cricetulus griseus. Expression_system_taxid: 10029.
Resolution:
2.31Å     R-factor:   0.200     R-free:   0.251
Authors: F.Nachon,E.Carletti
Key ref: E.Carletti et al. (2008). Aging of cholinesterases phosphylated by tabun proceeds through O-dealkylation. J Am Chem Soc, 130, 16011-16020. PubMed id: 18975951 DOI: 10.1021/ja804941z
Date:
25-Jun-08     Release date:   02-Dec-08    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P06276  (CHLE_HUMAN) -  Cholinesterase
Seq:
Struc:
 
Seq:
Struc:
602 a.a.
527 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 5 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.3.1.1.8  - Cholinesterase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: An acylcholine + H2O = choline + a carboxylate
acylcholine
+ H(2)O
= choline
+ carboxylate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   7 terms 
  Biological process     response to drug   13 terms 
  Biochemical function     catalytic activity     9 terms  

 

 
    reference    
 
 
DOI no: 10.1021/ja804941z J Am Chem Soc 130:16011-16020 (2008)
PubMed id: 18975951  
 
 
Aging of cholinesterases phosphylated by tabun proceeds through O-dealkylation.
E.Carletti, H.Li, B.Li, F.Ekström, Y.Nicolet, M.Loiodice, E.Gillon, M.T.Froment, O.Lockridge, L.M.Schopfer, P.Masson, F.Nachon.
 
  ABSTRACT  
 
Human butyrylcholinesterase (hBChE) hydrolyzes or scavenges a wide range of toxic esters, including heroin, cocaine, carbamate pesticides, organophosphorus pesticides, and nerve agents. Organophosphates (OPs) exert their acute toxicity through inhibition of acetylcholinesterase (AChE) by phosphorylation of the catalytic serine. Phosphylated cholinesterase (ChE) can undergo a spontaneous, time-dependent process called "aging", during which the OP-ChE conjugate is dealkylated. This leads to irreversible inhibition of the enzyme. The inhibition of ChEs by tabun and the subsequent aging reaction are of particular interest, because tabun-ChE conjugates display an extraordinary resistance toward most current oxime reactivators. We investigated the structural basis of oxime resistance for phosphoramidated ChE conjugates by determining the crystal structures of the non-aged and aged forms of hBChE inhibited by tabun, and by updating the refinement of non-aged and aged tabun-inhibited mouse AChE (mAChE). Structures for non-aged and aged tabun-hBChE were refined to 2.3 and 2.1 A, respectively. The refined structures of aged ChE conjugates clearly show that the aging reaction proceeds through O-dealkylation of the P(R) enantiomer of tabun. After dealkylation, the negatively charged oxygen forms a strong salt bridge with protonated His438N epsilon2 that prevents reactivation. Mass spectrometric analysis of the aged tabun-inhibited hBChE showed that both the dimethylamine and ethoxy side chains were missing from the phosphorus. Loss of the ethoxy is consistent with the crystallography results. Loss of the dimethylamine is consistent with acid-catalyzed deamidation during the preparation of the aged adduct for mass spectrometry. The reported 3D data will help in the design of new oximes capable of reactivating tabun-ChE conjugates.
 

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.  
21091433 F.Nachon, E.Carletti, M.Wandhammer, Y.Nicolet, L.M.Schopfer, P.Masson, and O.Lockridge (2011).
X-ray crystallographic snapshots of reaction intermediates in the G117H mutant of human butyrylcholinesterase, a nerve agent target engineered into a catalytic bioscavenger.
  Biochem J, 434, 73-82.
PDB codes: 2xmb 2xmc 2xmd 2xmg
20004171 P.Masson, and O.Lockridge (2010).
Butyrylcholinesterase for protection from organophosphorus poisons: catalytic complexities and hysteretic behavior.
  Arch Biochem Biophys, 494, 107-120.  
19368529 E.Carletti, N.Aurbek, E.Gillon, M.Loiodice, Y.Nicolet, J.C.Fontecilla-Camps, P.Masson, H.Thiermann, F.Nachon, and F.Worek (2009).
Structure-activity analysis of aging and reactivation of human butyrylcholinesterase inhibited by analogues of tabun.
  Biochem J, 421, 97.
PDB codes: 2wid 2wif 2wig 2wij 2wik 2wil 2wsl
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.