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| | <StructureSection load='2x8b' size='340' side='right'caption='[[2x8b]], [[Resolution|resolution]] 2.95Å' scene=''> | | <StructureSection load='2x8b' size='340' side='right'caption='[[2x8b]], [[Resolution|resolution]] 2.95Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2x8b]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Dendroaspis_angusticeps Dendroaspis angusticeps] and [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2X8B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2X8B FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2x8b]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Dendroaspis_angusticeps Dendroaspis angusticeps] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2X8B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2X8B FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</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]] 2.95Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEN:O-[N,N-DIMETHYLPHOSPHORAMIDATE]-L-SERINE'>SEN</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SEN:O-[N,N-DIMETHYLPHOSPHORAMIDATE]-L-SERINE'>SEN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1fsc|1fsc]], [[1mah|1mah]], [[1ku6|1ku6]], [[2clj|2clj]], [[1b41|1b41]], [[1puv|1puv]], [[1fss|1fss]], [[1puw|1puw]], [[1vzj|1vzj]], [[1f8u|1f8u]]</div></td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Acetylcholinesterase Acetylcholinesterase], with EC number [https://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=2x8b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2x8b OCA], [https://pdbe.org/2x8b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2x8b RCSB], [https://www.ebi.ac.uk/pdbsum/2x8b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2x8b ProSAT]</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=2x8b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2x8b OCA], [https://pdbe.org/2x8b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2x8b RCSB], [https://www.ebi.ac.uk/pdbsum/2x8b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2x8b ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[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> [[https://www.uniprot.org/uniprot/TXFA2_DENAN TXFA2_DENAN]] This three-finger toxin selectively binds and inhibits with a 1:1 stoichiometry the mammalian and electric fish acetylcholinesterase (AChE) at picomolar concentrations. It is highly specific for the peripheral site on acetylcholinesterase. It has been called fasciculin since after injection into mice it cause severe, generalized and long-lasting (5-7 hours) fasciculations. The whole venom has anticoagulant activity, and the various components seem to act synergistically.
| + | [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> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Acetylcholinesterase]] | |
| | [[Category: Dendroaspis angusticeps]] | | [[Category: Dendroaspis angusticeps]] |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Carletti, E]] | + | [[Category: Carletti E]] |
| - | [[Category: Colletier, J P]] | + | [[Category: Colletier JP]] |
| - | [[Category: Nachon, F]] | + | [[Category: Nachon F]] |
| - | [[Category: Aging]]
| + | |
| - | [[Category: Blood group antigen]]
| + | |
| - | [[Category: Cell junction]]
| + | |
| - | [[Category: Gpi-anchor]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase-toxin complex]]
| + | |
| - | [[Category: Neurotransmitter degradation]]
| + | |
| - | [[Category: Serine esterase]]
| + | |
| - | [[Category: Tabun]]
| + | |
| Structural highlights
2x8b is a 2 chain structure with sequence from Dendroaspis angusticeps and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.95Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Tabun is a warfare agent that inhibits human acetylcholinesterase (hAChE) by rapid phosphylation of the catalytic serine. A time-dependent reaction occurs on the tabun adduct, leading to an "aged" enzyme, resistant to oxime reactivators. The aging reaction may proceed via either dealkylation or deamidation, depending on the stereochemistry of the phosphoramidyl adduct. We solved the X-ray structure of aged tabun-hAChE complexed with fasciculin II, and we show that aging proceeds through O-dealkylation, in agreement with the aging mechanism that we determined for tabun-inhibited human butyrylcholinesterase and mouse acetylcholinesterase. Noteworthy, aging and binding of fasciculin II lead to an improved thermostability, resulting from additional stabilizing interactions between the two subdomains that face each other across the active site gorge. This first structure of hAChE inhibited by a nerve agent provides structural insight into the inhibition and aging mechanisms and a structural template for the design of molecules capable of reactivating aged hAChE.
Structural Evidence That Human Acetylcholinesterase Inhibited by Tabun Ages through O-Dealkylation.,Carletti E, Colletier JP, Dupeux F, Trovaslet M, Masson P, Nachon F J Med Chem. 2010 Apr 21. PMID:20408548[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
- ↑ Carletti E, Colletier JP, Dupeux F, Trovaslet M, Masson P, Nachon F. Structural Evidence That Human Acetylcholinesterase Inhibited by Tabun Ages through O-Dealkylation. J Med Chem. 2010 Apr 21. PMID:20408548 doi:10.1021/jm901853b
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