View source for 7awh


==Crystal structure of human butyrylcholinesterase in complex with tert-butyl 3-(((2-((1-(benzenesulfonyl)-1H-indol-4-yl)oxy)ethyl)amino)methyl)piperidine-1-carboxylate==
<StructureSection load='7awh' size='340' side='right'caption='[[7awh]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7awh]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AWH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AWH FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=S8K:~{tert}-butyl+(3~{S})-3-[[2-[1-(phenylsulfonyl)indol-4-yl]oxyethylamino]methyl]piperidine-1-carboxylate'>S8K</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Cholinesterase Cholinesterase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.8 3.1.1.8] </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=7awh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7awh OCA], [https://pdbe.org/7awh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7awh RCSB], [https://www.ebi.ac.uk/pdbsum/7awh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7awh ProSAT]</span></td></tr>
</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 ==
The lack of an effective treatment makes Alzheimer's disease a serious healthcare problem and a challenge for medicinal chemists. Herein we report interdisciplinary research on novel multifunctional ligands targeting proteins and processes involved in the development of the disease: BuChE, 5-HT6 receptors and beta-amyloid aggregation. Structure-activity relationship analyses supported by crystallography and docking studies led to the identification of a fused-type multifunctional ligand 50, with remarkable and balanced potencies against BuChE (IC50 = 90 nM) and 5-HT6R (Ki = 4.8 nM), and inhibitory activity against Abeta aggregation (53% at 10 muM). In in vitro ADME-Tox and in vivo pharmacokinetic studies compound 50 showed good stability in the mouse liver microsomes, favourable safety profile and brain permeability with the brain to plasma ratio of 6.79 after p.o. administration in mice, thus being a promising candidate for in vivo pharmacology studies and a solid foundation for further research on effective anti-AD therapies.

Development and crystallography-aided SAR studies of multifunctional BuChE inhibitors and 5-HT6R antagonists with beta-amyloid anti-aggregation properties.,Wichur T, Godyn J, Goral I, Latacz G, Bucki A, Siwek A, Gluch-Lutwin M, Mordyl B, Sniecikowska J, Walczak M, Knez D, Jukic M, Salat K, Gobec S, Kolaczkowski M, Malawska B, Brazzolotto X, Wieckowska A Eur J Med Chem. 2021 Aug 27;225:113792. doi: 10.1016/j.ejmech.2021.113792. PMID:34530376<ref>PMID:34530376</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7awh" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Cholinesterase]]
[[Category: Large Structures]]
[[Category: Brazzolotto, X]]
[[Category: Wichur, T]]
[[Category: Wieckowska, A]]
[[Category: Butyrylcholinesterase]]
[[Category: Hydrolase]]
[[Category: Inhibitor complex]]