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==Crystal structure of human acetylcholinesterase in complex with C35.== | ==Crystal structure of human acetylcholinesterase in complex with C35.== | ||
<StructureSection load='6f25' size='340' side='right' caption='[[6f25]], [[Resolution|resolution]] 3.05Å' scene=''> | <StructureSection load='6f25' size='340' side='right'caption='[[6f25]], [[Resolution|resolution]] 3.05Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6f25]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6F25 OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6f25]] 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=6F25 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6F25 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=CVZ:3-[(~{E})-5-[ethyl-[(2-nitrophenyl)methyl]amino]pent-1-enyl]-1-[5-[ethyl-[(2-nitrophenyl)methyl]amino]pentyl]-6-methyl-pyrimidine-2,4-dione'>CVZ</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.0519965Å</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=CVZ:3-[(~{E})-5-[ethyl-[(2-nitrophenyl)methyl]amino]pent-1-enyl]-1-[5-[ethyl-[(2-nitrophenyl)methyl]amino]pentyl]-6-methyl-pyrimidine-2,4-dione'>CVZ</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6f25 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f25 OCA], [https://pdbe.org/6f25 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6f25 RCSB], [https://www.ebi.ac.uk/pdbsum/6f25 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6f25 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> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Profound synaptic dysfunction contributes to early loss of short-term memory in Alzheimer's disease. This study was set up to analyze possible neuroprotective effects of two dual binding site inhibitors of acetylcholinesterase (AChE), a new 6-methyluracil derivative, C-35, and the clinically used inhibitor donepezil. Crystal structure of the complex between human AChE and C-35 revealed tight contacts of ligand along the enzyme active site gorge. Molecular dynamics simulations indicated that the external flexible part of the ligand establishes multiple transient interactions with the enzyme peripheral anionic site. Thus, C-35 is a dual binding site inhibitor of AChE. In transgenic mice, expressing a chimeric mouse/human amyloid precursor protein and a human presenilin-1 mutant, C-35 (5mg/kg, i.p) and donepezil (0.75mg/kg, i.p) partially reversed synapse loss, decreased the number of amyloid plaques, and restored learning and memory. To separate temporal symptomatic therapeutic effects, associated with the increased lifetime of acetylcholine in the brain, from possible disease-modifying effect, an experimental protocol based on drug withdrawal from therapy was performed. When administration of C-35 and donepezil was terminated three weeks after the trial started, animals that were receiving C-35 showed a much better ability to learn than those who received vehicle or donepezil. Our results provide additional evidence that dual binding site inhibitors of AChE have Alzheimer's disease-modifying action. | |||
New evidence for dual binding site inhibitors of acetylcholinesterase as improved drugs for treatment of Alzheimer's disease.,Zueva I, Dias J, Lushchekina S, Semenov V, Mukhamedyarov M, Pashirova T, Babaev V, Nachon F, Petrova N, Nurullin L, Zakharova L, Ilyin V, Masson P, Petrov K Neuropharmacology. 2019 Sep 1;155:131-141. doi: 10.1016/j.neuropharm.2019.05.025., Epub 2019 May 25. PMID:31132435<ref>PMID:31132435</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6f25" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Acetylcholinesterase 3D structures|Acetylcholinesterase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Dias J]] | ||
[[Category: | [[Category: Nachon F]] | ||
Latest revision as of 12:54, 23 October 2024
Crystal structure of human acetylcholinesterase in complex with C35.Crystal structure of human acetylcholinesterase in complex with C35.
Structural highlights
FunctionACES_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 PubMedProfound synaptic dysfunction contributes to early loss of short-term memory in Alzheimer's disease. This study was set up to analyze possible neuroprotective effects of two dual binding site inhibitors of acetylcholinesterase (AChE), a new 6-methyluracil derivative, C-35, and the clinically used inhibitor donepezil. Crystal structure of the complex between human AChE and C-35 revealed tight contacts of ligand along the enzyme active site gorge. Molecular dynamics simulations indicated that the external flexible part of the ligand establishes multiple transient interactions with the enzyme peripheral anionic site. Thus, C-35 is a dual binding site inhibitor of AChE. In transgenic mice, expressing a chimeric mouse/human amyloid precursor protein and a human presenilin-1 mutant, C-35 (5mg/kg, i.p) and donepezil (0.75mg/kg, i.p) partially reversed synapse loss, decreased the number of amyloid plaques, and restored learning and memory. To separate temporal symptomatic therapeutic effects, associated with the increased lifetime of acetylcholine in the brain, from possible disease-modifying effect, an experimental protocol based on drug withdrawal from therapy was performed. When administration of C-35 and donepezil was terminated three weeks after the trial started, animals that were receiving C-35 showed a much better ability to learn than those who received vehicle or donepezil. Our results provide additional evidence that dual binding site inhibitors of AChE have Alzheimer's disease-modifying action. New evidence for dual binding site inhibitors of acetylcholinesterase as improved drugs for treatment of Alzheimer's disease.,Zueva I, Dias J, Lushchekina S, Semenov V, Mukhamedyarov M, Pashirova T, Babaev V, Nachon F, Petrova N, Nurullin L, Zakharova L, Ilyin V, Masson P, Petrov K Neuropharmacology. 2019 Sep 1;155:131-141. doi: 10.1016/j.neuropharm.2019.05.025., Epub 2019 May 25. PMID:31132435[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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