7amz
From Proteopedia
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==Crystal structure of human Butyrylcholinesterase in complex with N-((2S,3R)-4-((2,2-dimethylpropyl)amino)-3-hydroxy-1-phenylbutan-2-yl)-2,2-diphenylacetamide== | ==Crystal structure of human Butyrylcholinesterase in complex with N-((2S,3R)-4-((2,2-dimethylpropyl)amino)-3-hydroxy-1-phenylbutan-2-yl)-2,2-diphenylacetamide== | ||
| - | <StructureSection load='7amz' size='340' side='right'caption='[[7amz]]' scene=''> | + | <StructureSection load='7amz' size='340' side='right'caption='[[7amz]], [[Resolution|resolution]] 2.25Å' 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=7AMZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AMZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7amz]] is a 1 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=7AMZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AMZ 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=7amz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7amz OCA], [https://pdbe.org/7amz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7amz RCSB], [https://www.ebi.ac.uk/pdbsum/7amz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7amz ProSAT]</span></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]] 2.25Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=RNZ:2,2-dimethylpropyl-[(2~{R},3~{S})-3-(2,2-diphenylethanoylamino)-2-oxidanyl-4-phenyl-butyl]azanium'>RNZ</scene>, <scene name='pdbligand=SIA:O-SIALIC+ACID'>SIA</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'>[https://proteopedia.org/fgij/fg.htm?mol=7amz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7amz OCA], [https://pdbe.org/7amz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7amz RCSB], [https://www.ebi.ac.uk/pdbsum/7amz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7amz ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/CHLE_HUMAN CHLE_HUMAN] Defects in BCHE are the cause of butyrylcholinesterase deficiency (BChE deficiency) [MIM:[https://omim.org/entry/177400 177400]. BChE deficiency is a metabolic disorder characterized by prolonged apnoea after the use of certain anesthetic drugs, including the muscle relaxants succinylcholine or mivacurium and other ester local anesthetics. The duration of the prolonged apnoea varies significantly depending on the extent of the enzyme deficiency. BChE deficiency is a multifactorial disorder. The hereditary condition is transmitted as an autosomal recessive trait. | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/CHLE_HUMAN CHLE_HUMAN] Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.<ref>PMID:19542320</ref> <ref>PMID:19452557</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Looking for an effective anti-Alzheimer's agent is very challenging; however, a multifunctional ligand strategy may be a promising solution for the treatment of this complex disease. We herein present the design, synthesis and biological evaluation of novel hydroxyethylamine derivatives displaying unique, multiple properties that have not been previously reported. The original mechanism of action combines inhibitory activity against disease-modifying targets: beta-secretase enzyme (BACE1) and amyloid beta (Abeta) aggregation, along with an effect on targets associated with symptom relief - inhibition of butyrylcholinesterase (BuChE) and gamma-aminobutyric acid transporters (GATs). Among the obtained molecules, compound 36 exhibited the most balanced and broad activity profile (eeAChE IC50 = 2.86 muM; eqBuChE IC50 = 60 nM; hBuChE IC50 = 20 nM; hBACE1 IC50 = 5.9 muM; inhibition of Abeta aggregation = 57.9% at 10 muM; mGAT1 IC50 = 10.96 muM; and mGAT2 IC50 = 19.05 muM). Moreover, we also identified 31 as the most potent mGAT4 and hGAT3 inhibitor (IC50 = 5.01 muM and IC50 = 2.95 muM, respectively), with high selectivity over other subtypes. Compounds 36 and 31 represent new anti-Alzheimer agents that can ameliorate cognitive decline and modify the progress of disease. | ||
| + | |||
| + | Discovery of multifunctional anti-Alzheimer's agents with a unique mechanism of action including inhibition of the enzyme butyrylcholinesterase and gamma-aminobutyric acid transporters.,Pasieka A, Panek D, Jonczyk J, Godyn J, Szalaj N, Latacz G, Tabor J, Mezeiova E, Chantegreil F, Dias J, Knez D, Lu J, Pi R, Korabecny J, Brazzolotto X, Gobec S, Hofner G, Wanner K, Wieckowska A, Malawska B Eur J Med Chem. 2021 Jun 5;218:113397. doi: 10.1016/j.ejmech.2021.113397. Epub, 2021 Mar 31. PMID:33838585<ref>PMID:33838585</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7amz" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Butyrylcholinesterase 3D structures|Butyrylcholinesterase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Brazzolotto X]] | [[Category: Brazzolotto X]] | ||
Revision as of 12:12, 1 February 2024
Crystal structure of human Butyrylcholinesterase in complex with N-((2S,3R)-4-((2,2-dimethylpropyl)amino)-3-hydroxy-1-phenylbutan-2-yl)-2,2-diphenylacetamide
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