7aiv: Difference between revisions
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==Crystal structure of Torpedo Californica acetylcholinesterase in complex with 4-{[(3-Chloro-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b]quinolin-12-yl)amino]methyl}-N-(4-hydroxy-3-methoxybenzyl)benzamide== | ==Crystal structure of Torpedo Californica acetylcholinesterase in complex with 4-{[(3-Chloro-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b]quinolin-12-yl)amino]methyl}-N-(4-hydroxy-3-methoxybenzyl)benzamide== | ||
<StructureSection load='7aiv' size='340' side='right'caption='[[7aiv]]' scene=''> | <StructureSection load='7aiv' size='340' side='right'caption='[[7aiv]], [[Resolution|resolution]] 2.55Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AIV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AIV FirstGlance]. <br> | <table><tr><td colspan='2'>[[7aiv]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Tetronarce_californica Tetronarce californica]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AIV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AIV FirstGlance]. <br> | ||
</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=7aiv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7aiv OCA], [https://pdbe.org/7aiv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7aiv RCSB], [https://www.ebi.ac.uk/pdbsum/7aiv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7aiv ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8UE:4-{[(3-Chloro-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b]quinolin-12-yl)amino]methyl}-N-(4-hydroxy-3-methoxybenzyl)benzamide'>8UE</scene></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=7aiv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7aiv OCA], [https://pdbe.org/7aiv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7aiv RCSB], [https://www.ebi.ac.uk/pdbsum/7aiv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7aiv ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://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 == | |||
The combination of the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that retain or improve the antioxidant properties of capsaicin. Crystal structures of their complexes with AChE and BChE revealed the molecular basis for their high potency. Brain penetration was confirmed by biodistribution studies in C57BL6 mice, with one compound (5i) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, i.p., 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by three different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced Abeta42/Abeta40 ratio in the hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound 5i emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms. | |||
Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice.,Viayna E, Coquelle N, Cieslikiewicz-Bouet M, Cisternas P, Oliva CA, Sanchez-Lopez E, Ettcheto M, Bartolini M, De Simone A, Ricchini M, Rendina M, Pons M, Firuzi O, Perez B, Saso L, Andrisano V, Nachon F, Brazzolotto X, Garcia ML, Camins A, Silman I, Jean L, Inestrosa NC, Colletier JP, Renard PY, Munoz-Torrero D J Med Chem. 2021 Jan 14;64(1):812-839. doi: 10.1021/acs.jmedchem.0c01775. Epub, 2020 Dec 28. PMID:33356266<ref>PMID:33356266</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7aiv" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Acetylcholinesterase]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Colletier | [[Category: Tetronarce californica]] | ||
[[Category: Coquelle N]] | [[Category: Colletier, J P]] | ||
[[Category: Coquelle, N]] | |||
[[Category: Ad]] | |||
[[Category: Alzheimer disease]] | |||
[[Category: Hydrolase]] | |||
[[Category: Torpedo californica acetylcholinesterase]] | |||
Revision as of 16:02, 4 May 2022
Crystal structure of Torpedo Californica acetylcholinesterase in complex with 4-{[(3-Chloro-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b]quinolin-12-yl)amino]methyl}-N-(4-hydroxy-3-methoxybenzyl)benzamideCrystal structure of Torpedo Californica acetylcholinesterase in complex with 4-{[(3-Chloro-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b]quinolin-12-yl)amino]methyl}-N-(4-hydroxy-3-methoxybenzyl)benzamide
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 PubMedThe combination of the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that retain or improve the antioxidant properties of capsaicin. Crystal structures of their complexes with AChE and BChE revealed the molecular basis for their high potency. Brain penetration was confirmed by biodistribution studies in C57BL6 mice, with one compound (5i) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, i.p., 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by three different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced Abeta42/Abeta40 ratio in the hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound 5i emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms. Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice.,Viayna E, Coquelle N, Cieslikiewicz-Bouet M, Cisternas P, Oliva CA, Sanchez-Lopez E, Ettcheto M, Bartolini M, De Simone A, Ricchini M, Rendina M, Pons M, Firuzi O, Perez B, Saso L, Andrisano V, Nachon F, Brazzolotto X, Garcia ML, Camins A, Silman I, Jean L, Inestrosa NC, Colletier JP, Renard PY, Munoz-Torrero D J Med Chem. 2021 Jan 14;64(1):812-839. doi: 10.1021/acs.jmedchem.0c01775. Epub, 2020 Dec 28. PMID:33356266[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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