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| | ==Crystal Structure of Recombinant Human Acetylcholinesterase Inhibited by (-) Stereoisomer of VX== | | ==Crystal Structure of Recombinant Human Acetylcholinesterase Inhibited by (-) Stereoisomer of VX== |
| - | <StructureSection load='6cqt' size='340' side='right' caption='[[6cqt]], [[Resolution|resolution]] 2.27Å' scene=''> | + | <StructureSection load='6cqt' size='340' side='right'caption='[[6cqt]], [[Resolution|resolution]] 2.27Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6cqt]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CQT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CQT FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6cqt]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CQT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CQT FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7PE:2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL'>7PE</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=VX:O-ETHYLMETHYLPHOSPHONIC+ACID+ESTER+GROUP'>VX</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.273Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6cqu|6cqu]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7PE:2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL'>7PE</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=VX:O-ETHYLMETHYLPHOSPHONIC+ACID+ESTER+GROUP'>VX</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=6cqt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cqt OCA], [https://pdbe.org/6cqt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6cqt RCSB], [https://www.ebi.ac.uk/pdbsum/6cqt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6cqt ProSAT]</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=6cqt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cqt OCA], [http://pdbe.org/6cqt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cqt RCSB], [http://www.ebi.ac.uk/pdbsum/6cqt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cqt ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == 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> | + | [https://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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6cqt" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6cqt" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Acetylcholinesterase 3D structures|Acetylcholinesterase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Acetylcholinesterase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Bester, S M]] | + | [[Category: Large Structures]] |
| - | [[Category: Guelta, M A]] | + | [[Category: Bester SM]] |
| - | [[Category: Height, J J]] | + | [[Category: Guelta MA]] |
| - | [[Category: Pegan, S D]] | + | [[Category: Height JJ]] |
| - | [[Category: Hydrolase]] | + | [[Category: Pegan SD]] |
| Structural highlights
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
Over 50 years ago, the toxicity of irreversible organophosphate inhibitors targeting human acetylcholinesterase (hAChE) were observed to be stereospecific. The therapeutic reversal of hAChE inhibition by reactivators has also been shown to depend on the stereochemistry of the inhibitor. To gain clarity on the mechanism of stereospecific inhibition, the X-ray crystallographic structures hAChE inhibited by a racemic mixture of VX (PR/S) and its enantiomers were obtained. Beyond identifying hAChE structural features that lend themselves to stereospecific inhibition, structures of the reactivator HI-6 bound to hAChEs inhibited by VX enantiomers of varying toxicity, or in its uninhibited state, were obtained. Comparison of hAChE in these pre-reactivation and post-reactivation states along with enzymatic data reveals the potential influence of unproductive reactivator poses on the efficacy of these types of therapeutics. The recognition of structural features related to hAChE's stereospecificity towards VX shed light on the molecular influences of toxicity and their effect on reactivators. In addition to providing a better understanding of the innate issues with current reactivators, an avenue for improvement of reactivators is envisioned.
Structural insights of stereospecific inhibition of human acetylcholinesterase by VX and subsequent reactivation by HI-6.,Bester SM, Guelta MA, Cheung J, Winemiller MD, Bae SY, Myslinski J, Pegan SD, Height JJ Chem Res Toxicol. 2018 Nov 21. doi: 10.1021/acs.chemrestox.8b00294. PMID:30462502[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Bester SM, Guelta MA, Cheung J, Winemiller MD, Bae SY, Myslinski J, Pegan SD, Height JJ. Structural insights of stereospecific inhibition of human acetylcholinesterase by VX and subsequent reactivation by HI-6. Chem Res Toxicol. 2018 Nov 21. doi: 10.1021/acs.chemrestox.8b00294. PMID:30462502 doi:http://dx.doi.org/10.1021/acs.chemrestox.8b00294
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