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PDBsum entry 2whq

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protein ligands Protein-protein interface(s) links
Hydrolase PDB id
2whq
Jmol
Contents
Protein chains
535 a.a. *
Ligands
NAG ×3
HI6 ×2
P6G
PGE ×4
PEG
Waters ×650
* Residue conservation analysis
PDB id:
2whq
Name: Hydrolase
Title: Crystal structure of acetylcholinesterase, phosphonylated by sarin (aged) in complex with hi-6
Structure: Acetylcholinesterase. Chain: a, b. Fragment: catalytic domain, residues 32-574. Synonym: ache. Engineered: yes. Other_details: catalytic ser203 phosphonylated by sarin. The complex was subsequently aged
Source: Mus musculus. Mouse. Organism_taxid: 10090. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: human embryonic kidney (hek) 293 cells.
Resolution:
2.15Å     R-factor:   0.186     R-free:   0.211
Authors: F.Ekstrom,A.Hornberg,E.Artursson,L.G.Hammarstrom, G.Schneider,Y.P.Pang
Key ref: F.Ekström et al. (2009). Structure of HI-6*sarin-acetylcholinesterase determined by X-ray crystallography and molecular dynamics simulation: reactivator mechanism and design. PLoS One, 4, e5957. PubMed id: 19536291
Date:
06-May-09     Release date:   30-Jun-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P21836  (ACES_MOUSE) -  Acetylcholinesterase
Seq:
Struc:
 
Seq:
Struc:
614 a.a.
535 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   12 terms 
  Biological process     receptor internalization   8 terms 
  Biochemical function     carboxylic ester hydrolase activity     9 terms  

 

 
PLoS One 4:e5957 (2009)
PubMed id: 19536291  
 
 
Structure of HI-6*sarin-acetylcholinesterase determined by X-ray crystallography and molecular dynamics simulation: reactivator mechanism and design.
F.Ekström, A.Hörnberg, E.Artursson, L.G.Hammarström, G.Schneider, Y.P.Pang.
 
  ABSTRACT  
 
Organophosphonates such as isopropyl metylphosphonofluoridate (sarin) are extremely toxic as they phosphonylate the catalytic serine residue of acetylcholinesterase (AChE), an enzyme essential to humans and other species. Design of effective AChE reactivators as antidotes to various organophosphonates requires information on how the reactivators interact with the phosphonylated AChEs. However, such information has not been available hitherto because of three main challenges. First, reactivators are generally flexible in order to change from the ground state to the transition state for reactivation; this flexibility discourages determination of crystal structures of AChE in complex with effective reactivators that are intrinsically disordered. Second, reactivation occurs upon binding of a reactivator to the phosphonylated AChE. Third, the phosphorous conjugate can develop resistance to reactivation. We have identified crystallographic conditions that led to the determination of a crystal structure of the sarin(nonaged)-conjugated mouse AChE in complex with [(E)-[1-[(4-carbamoylpyridin-1-ium-1-yl)methoxymethyl]pyridin-2-ylidene]methyl]-oxoazanium dichloride (HI-6) at a resolution of 2.2 A. In this structure, the carboxyamino-pyridinium ring of HI-6 is sandwiched by Tyr124 and Trp286, however, the oxime-pyridinium ring is disordered. By combining crystallography with microsecond molecular dynamics simulation, we determined the oxime-pyridinium ring structure, which shows that the oxime group of HI-6 can form a hydrogen-bond network to the sarin isopropyl ether oxygen, and a water molecule is able to form a hydrogen bond to the catalytic histidine residue and subsequently deprotonates the oxime for reactivation. These results offer insights into the reactivation mechanism of HI-6 and design of better reactivators.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21451868 G.Mercey, T.Verdelet, G.Saint-André, E.Gillon, A.Wagner, R.Baati, L.Jean, F.Nachon, and P.Y.Renard (2011).
First efficient uncharged reactivators for the dephosphylation of poisoned human acetylcholinesterase.
  Chem Commun (Camb), 47, 5295-5297.  
21455295 Y.P.Pang, J.G.Park, S.Wang, A.Vummenthala, R.K.Mishra, J.E.McLaughlin, R.Di, J.N.Kahn, N.E.Tumer, L.Janosi, J.Davis, and C.B.Millard (2011).
Small-molecule inhibitor leads of ribosome-inactivating proteins developed using the doorstop approach.
  PLoS One, 6, e17883.  
19901994 Y.P.Pang, A.Vummenthala, R.K.Mishra, J.G.Park, S.Wang, J.Davis, C.B.Millard, and J.J.Schmidt (2009).
Potent new small-molecule inhibitor of botulinum neurotoxin serotype A endopeptidase developed by synthesis-based computer-aided molecular design.
  PLoS One, 4, e7730.  
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
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