6euc: Difference between revisions
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==Reactivating oxime bound to Tc AChE's catalytic gorge.== | ==Reactivating oxime bound to Tc AChE's catalytic gorge.== | ||
<StructureSection load='6euc' size='340' side='right' caption='[[6euc]], [[Resolution|resolution]] 2.22Å' scene=''> | <StructureSection load='6euc' size='340' side='right'caption='[[6euc]], [[Resolution|resolution]] 2.22Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6euc]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EUC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EUC FirstGlance]. <br> | <table><tr><td colspan='2'>[[6euc]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Pacific_electric_ray Pacific electric ray]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EUC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EUC FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=RM0:2-[(~{E})-hydroxyiminomethyl]-6-(5-morpholin-4-ylpentyl)pyridin-3-ol'>RM0</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=RM0:2-[(~{E})-hydroxyiminomethyl]-6-(5-morpholin-4-ylpentyl)pyridin-3-ol'>RM0</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ache ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=7787 Pacific electric ray])</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='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=6euc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6euc OCA], [http://pdbe.org/6euc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6euc RCSB], [http://www.ebi.ac.uk/pdbsum/6euc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6euc 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=6euc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6euc OCA], [http://pdbe.org/6euc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6euc RCSB], [http://www.ebi.ac.uk/pdbsum/6euc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6euc ProSAT]</span></td></tr> | ||
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== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/ACES_TETCF ACES_TETCF]] Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. May be involved in cell-cell interactions. | [[http://www.uniprot.org/uniprot/ACES_TETCF ACES_TETCF]] Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. May be involved in cell-cell interactions. | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
A new series of 3-hydroxy-2-pyridine aldoxime compounds have been designed, synthesised and tested in vitro, in silico, and ex vivo as reactivators of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibited by organophosphates (OPs), for example, VX, sarin, cyclosarin, tabun, and paraoxon. The reactivation rates of three oximes (16-18) were determined to be greater than that of 2-PAM and comparable to that of HI-6, two pyridinium aldoximes currently used by the armies of several countries. The interactions important for a productive orientation of the oxime group within the OP-inhibited enzyme have been clarified by molecular-modelling studies, and by the resolution of the crystal structure of the complex of oxime 17 with Torpedo californica AChE. Blood-brain barrier penetration was predicted for oximes 15-18 based on their physicochemical properties and an in vitro brain membrane permeation assay. Among the evaluated compounds, two morpholine-3-hydroxypyridine aldoxime conjugates proved to be promising reactivators of OP-inhibited cholinesterases. Moreover, efficient ex vivo reactivation of phosphylated native cholinesterases by selected oximes enabled significant hydrolysis of VX, sarin, paraoxon, and cyclosarin in whole human blood, which indicates that the oximes have scavenging potential. | |||
Potent 3-Hydroxy-2-Pyridine Aldoxime Reactivators of Organophosphate-Inhibited Cholinesterases with Predicted Blood-Brain Barrier Penetration.,Zorbaz T, Braiki A, Marakovic N, Renou J, de la Mora E, Macek Hrvat N, Katalinic M, Silman I, Sussman JL, Mercey G, Gomez C, Mougeot R, Perez B, Baati R, Nachon F, Weik M, Jean L, Kovarik Z, Renard PY Chemistry. 2018 Jul 5;24(38):9675-9691. doi: 10.1002/chem.201801394. Epub 2018, Jun 8. PMID:29672968<ref>PMID:29672968</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6euc" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Acetylcholinesterase 3D structures|Acetylcholinesterase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Acetylcholinesterase]] | [[Category: Acetylcholinesterase]] | ||
[[Category: Large Structures]] | |||
[[Category: Pacific electric ray]] | |||
[[Category: Braiki, A]] | [[Category: Braiki, A]] | ||
[[Category: Jean, L]] | [[Category: Jean, L]] | ||
Revision as of 11:40, 27 November 2019
Reactivating oxime bound to Tc AChE's catalytic gorge.Reactivating oxime bound to Tc AChE's catalytic gorge.
Structural highlights
Function[ACES_TETCF] Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. May be involved in cell-cell interactions. Publication Abstract from PubMedA new series of 3-hydroxy-2-pyridine aldoxime compounds have been designed, synthesised and tested in vitro, in silico, and ex vivo as reactivators of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibited by organophosphates (OPs), for example, VX, sarin, cyclosarin, tabun, and paraoxon. The reactivation rates of three oximes (16-18) were determined to be greater than that of 2-PAM and comparable to that of HI-6, two pyridinium aldoximes currently used by the armies of several countries. The interactions important for a productive orientation of the oxime group within the OP-inhibited enzyme have been clarified by molecular-modelling studies, and by the resolution of the crystal structure of the complex of oxime 17 with Torpedo californica AChE. Blood-brain barrier penetration was predicted for oximes 15-18 based on their physicochemical properties and an in vitro brain membrane permeation assay. Among the evaluated compounds, two morpholine-3-hydroxypyridine aldoxime conjugates proved to be promising reactivators of OP-inhibited cholinesterases. Moreover, efficient ex vivo reactivation of phosphylated native cholinesterases by selected oximes enabled significant hydrolysis of VX, sarin, paraoxon, and cyclosarin in whole human blood, which indicates that the oximes have scavenging potential. Potent 3-Hydroxy-2-Pyridine Aldoxime Reactivators of Organophosphate-Inhibited Cholinesterases with Predicted Blood-Brain Barrier Penetration.,Zorbaz T, Braiki A, Marakovic N, Renou J, de la Mora E, Macek Hrvat N, Katalinic M, Silman I, Sussman JL, Mercey G, Gomez C, Mougeot R, Perez B, Baati R, Nachon F, Weik M, Jean L, Kovarik Z, Renard PY Chemistry. 2018 Jul 5;24(38):9675-9691. doi: 10.1002/chem.201801394. Epub 2018, Jun 8. PMID:29672968[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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