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4tpk

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==Human butyrylcholinesterase in complex with N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-methoxyethyl)-2-naphthamide==
==Human butyrylcholinesterase in complex with N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-methoxyethyl)-2-naphthamide==
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<StructureSection load='4tpk' size='340' side='right' caption='[[4tpk]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
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<StructureSection load='4tpk' size='340' side='right'caption='[[4tpk]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4tpk]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4TPK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4TPK FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4tpk]] 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=4TPK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4TPK FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3F9:N-{[(3R)-1-(2,3-DIHYDRO-1H-INDEN-2-YL)PIPERIDIN-3-YL]METHYL}-N-(2-METHOXYETHYL)NAPHTHALENE-2-CARBOXAMIDE'>3F9</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=FUL:BETA-L-FUCOSE'>FUL</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4bds|4bds]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3F9:N-{[(3R)-1-(2,3-DIHYDRO-1H-INDEN-2-YL)PIPERIDIN-3-YL]METHYL}-N-(2-METHOXYETHYL)NAPHTHALENE-2-CARBOXAMIDE'>3F9</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=FUL:BETA-L-FUCOSE'>FUL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cholinesterase Cholinesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.8 3.1.1.8] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4tpk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tpk OCA], [https://pdbe.org/4tpk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4tpk RCSB], [https://www.ebi.ac.uk/pdbsum/4tpk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4tpk ProSAT]</span></td></tr>
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<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=4tpk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tpk OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4tpk RCSB], [http://www.ebi.ac.uk/pdbsum/4tpk PDBsum]</span></td></tr>
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</table>
</table>
== Disease ==
== Disease ==
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[[http://www.uniprot.org/uniprot/CHLE_HUMAN CHLE_HUMAN]] Defects in BCHE are the cause of butyrylcholinesterase deficiency (BChE deficiency) [MIM:[http://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.
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[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 ==
== Function ==
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[[http://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>
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Butyrylcholinesterase (BChE) is regarded as a promising drug target as its levels and activity significantly increase in the late stages of Alzheimer's disease. To discover novel BChE inhibitors, we used a hierarchical virtual screening protocol followed by biochemical evaluation of 40 highest scoring hit compounds. Three of the compounds identified showed significant inhibitory activities against BChE. The most potent, compound 1 (IC50 = 21.3 nM), was resynthesized and resolved into its pure enantiomers. A high degree of stereoselective activity was revealed, and a dissociation constant of 2.7 nM was determined for the most potent stereoisomer (+)-1. The crystal structure of human BChE in complex with compound (+)-1 was solved, revealing the binding mode and providing clues for potential optimization. Additionally, compound 1 inhibited amyloid beta1-42 peptide self-induced aggregation into fibrils (by 61.7% at 10 muM) and protected cultured SH-SY5Y cells against amyloid-beta-induced toxicity. These data suggest that compound 1 represents a promising candidate for hit-to-lead follow-up in the drug-discovery process against Alzheimer's disease.
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Discovery, biological evaluation, and crystal structure of a novel nanomolar selective butyrylcholinesterase inhibitor.,Brus B, Kosak U, Turk S, Pislar A, Coquelle N, Kos J, Stojan J, Colletier JP, Gobec S J Med Chem. 2014 Oct 9;57(19):8167-79. doi: 10.1021/jm501195e. Epub 2014 Sep 29. PMID:25226236<ref>PMID:25226236</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Cholinesterase]]
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[[Category: Homo sapiens]]
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[[Category: Brus, B]]
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[[Category: Large Structures]]
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[[Category: Colletier, J P]]
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[[Category: Brus B]]
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[[Category: Coquelle, N]]
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[[Category: Colletier JP]]
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[[Category: Gobec, S]]
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[[Category: Coquelle N]]
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[[Category: Butyrylcholinesterase inhibition]]
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[[Category: Gobec S]]
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[[Category: Hydrolase]]
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Current revision

Human butyrylcholinesterase in complex with N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-methoxyethyl)-2-naphthamide

PDB ID 4tpk

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