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'''Unreleased structure'''


The entry 5hf8 is ON HOLD until Paper Publication
==Crystal structure of human acetylcholinesterase in complex with paraoxon (alternative acyl loop conformation)==
<StructureSection load='5hf8' size='340' side='right' caption='[[5hf8]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5hf8]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HF8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HF8 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DEP:DIETHYL+PHOSPHONATE'>DEP</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=EFS:ETHYL+DIHYDROGEN+PHOSPHATE'>EFS</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5hf5|5hf5]], [[5hf6|5hf6]], [[5hf9|5hf9]], [[5hfa|5hfa]]</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Acetylcholinesterase Acetylcholinesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.7 3.1.1.7] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5hf8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hf8 OCA], [http://pdbe.org/5hf8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hf8 RCSB], [http://www.ebi.ac.uk/pdbsum/5hf8 PDBsum]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/ACES_HUMAN ACES_HUMAN]] Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis.<ref>PMID:2714437</ref> <ref>PMID:1748670</ref> <ref>PMID:1517212</ref> <ref>PMID:11985878</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Irreversible inhibition of the essential nervous system enzyme acetylcholinesterase by organophosphate nerve agents and pesticides may quickly lead to death. Oxime reactivators currently used as antidotes are generally less effective against pesticide exposure than nerve agent exposure, and pesticide exposure constitutes the majority of cases of organophosphate poisoning in the world. The current lack of published structural data specific to human acetylcholinesterase organophosphate-inhibited and oxime-bound states hinders development of effective medical treatments. We have solved structures of human acetylcholinesterase in different states in complex with the organophosphate insecticide, paraoxon, and oximes. Reaction with paraoxon results in a highly perturbed acyl loop that causes a narrowing of the gorge in the peripheral site that may impede entry of reactivators. This appears characteristic of acetylcholinesterase inhibition by organophosphate insecticides but not nerve agents. Additional changes seen at the dimer interface are novel and provide further examples of the disruptive effect of paraoxon. Ternary structures of paraoxon-inhibited human acetylcholinesterase in complex with the oximes HI6 and 2-PAM reveals relatively poor positioning for reactivation. This study provides a structural foundation for improved reactivator design for the treatment of organophosphate intoxication. This article is protected by copyright. All rights reserved.


Authors: Franklin, M.F., Rudolph, M.J., Ginter, C., Cassidy, M.S., Cheung, J.
Structures of paraoxon-inhibited human acetylcholinesterase reveal perturbations of the acyl loop and the dimer interface.,Franklin MC, Rudolph MJ, Ginter C, Cassidy MS, Cheung J Proteins. 2016 May 18. doi: 10.1002/prot.25073. PMID:27191504<ref>PMID:27191504</ref>


Description: Crystal structure of human acetylcholinesterase in complex with paraoxon (alternative acyl loop conformation)
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
<div class="pdbe-citations 5hf8" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Acetylcholinesterase]]
[[Category: Cassidy, M S]]
[[Category: Cheung, J]]
[[Category: Franklin, M F]]
[[Category: Ginter, C]]
[[Category: Ginter, C]]
[[Category: Rudolph, M.J]]
[[Category: Rudolph, M J]]
[[Category: Franklin, M.F]]
[[Category: Hydrolase]]
[[Category: Cassidy, M.S]]
[[Category: Cheung, J]]

Revision as of 02:14, 24 June 2016

Crystal structure of human acetylcholinesterase in complex with paraoxon (alternative acyl loop conformation)Crystal structure of human acetylcholinesterase in complex with paraoxon (alternative acyl loop conformation)

Structural highlights

5hf8 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, , , , ,
Activity:Acetylcholinesterase, with EC number 3.1.1.7
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum

Function

[ACES_HUMAN] Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis.[1] [2] [3] [4]

Publication Abstract from PubMed

Irreversible inhibition of the essential nervous system enzyme acetylcholinesterase by organophosphate nerve agents and pesticides may quickly lead to death. Oxime reactivators currently used as antidotes are generally less effective against pesticide exposure than nerve agent exposure, and pesticide exposure constitutes the majority of cases of organophosphate poisoning in the world. The current lack of published structural data specific to human acetylcholinesterase organophosphate-inhibited and oxime-bound states hinders development of effective medical treatments. We have solved structures of human acetylcholinesterase in different states in complex with the organophosphate insecticide, paraoxon, and oximes. Reaction with paraoxon results in a highly perturbed acyl loop that causes a narrowing of the gorge in the peripheral site that may impede entry of reactivators. This appears characteristic of acetylcholinesterase inhibition by organophosphate insecticides but not nerve agents. Additional changes seen at the dimer interface are novel and provide further examples of the disruptive effect of paraoxon. Ternary structures of paraoxon-inhibited human acetylcholinesterase in complex with the oximes HI6 and 2-PAM reveals relatively poor positioning for reactivation. This study provides a structural foundation for improved reactivator design for the treatment of organophosphate intoxication. This article is protected by copyright. All rights reserved.

Structures of paraoxon-inhibited human acetylcholinesterase reveal perturbations of the acyl loop and the dimer interface.,Franklin MC, Rudolph MJ, Ginter C, Cassidy MS, Cheung J Proteins. 2016 May 18. doi: 10.1002/prot.25073. PMID:27191504[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Chhajlani V, Derr D, Earles B, Schmell E, August T. Purification and partial amino acid sequence analysis of human erythrocyte acetylcholinesterase. FEBS Lett. 1989 Apr 24;247(2):279-82. PMID:2714437
  2. ↑ Velan B, Grosfeld H, Kronman C, Leitner M, Gozes Y, Lazar A, Flashner Y, Marcus D, Cohen S, Shafferman A. The effect of elimination of intersubunit disulfide bonds on the activity, assembly, and secretion of recombinant human acetylcholinesterase. Expression of acetylcholinesterase Cys-580----Ala mutant. J Biol Chem. 1991 Dec 15;266(35):23977-84. PMID:1748670
  3. ↑ Shafferman A, Kronman C, Flashner Y, Leitner M, Grosfeld H, Ordentlich A, Gozes Y, Cohen S, Ariel N, Barak D, et al.. Mutagenesis of human acetylcholinesterase. Identification of residues involved in catalytic activity and in polypeptide folding. J Biol Chem. 1992 Sep 5;267(25):17640-8. PMID:1517212
  4. ↑ Yang L, He HY, Zhang XJ. Increased expression of intranuclear AChE involved in apoptosis of SK-N-SH cells. Neurosci Res. 2002 Apr;42(4):261-8. PMID:11985878
  5. ↑ Franklin MC, Rudolph MJ, Ginter C, Cassidy MS, Cheung J. Structures of paraoxon-inhibited human acetylcholinesterase reveal perturbations of the acyl loop and the dimer interface. Proteins. 2016 May 18. doi: 10.1002/prot.25073. PMID:27191504 doi:http://dx.doi.org/10.1002/prot.25073

5hf8, resolution 2.80Å

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