View source for 7qhe


==Human Butyrylcholinesterase in complex with (S)-1-(4-((naphthalen-1-yl)carbamoyl)benzyl)-N-(3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperidine-3-carboxamide==
<StructureSection load='7qhe' size='340' side='right'caption='[[7qhe]], [[Resolution|resolution]] 2.47&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7qhe]] 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=7QHE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QHE FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.47&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C4I:(3~{S})-1-[[4-(naphthalen-1-ylcarbamoyl)phenyl]methyl]-~{N}-[3-(1,2,3,4-tetrahydroacridin-9-ylamino)propyl]piperidine-3-carboxamide'>C4I</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <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=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=7qhe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qhe OCA], [https://pdbe.org/7qhe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qhe RCSB], [https://www.ebi.ac.uk/pdbsum/7qhe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qhe 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 ==
Butyrylcholinesterase is regarded as a promising drug target in advanced Alzheimer's disease. In order to identify highly selective and potent BuChE inhibitors, a 53-membered compound library was constructed via the oxime-based tethering approach based on microscale synthesis. Although A2Q17 and A3Q12 exhibited higher BuChE selectivity versus acetylcholinesterase, the inhibitory activities were unsatisfactory and A3Q12 did not inhibit Abeta(1-42) peptide self-induced aggregation. With A2Q17 and A3Q12 as leads, a novel series of tacrine derivatives with nitrogen-containing heterocycles were designed based on conformation restriction strategy. The results demonstrated that 39 (IC(50) = 3.49 nM) and 43 (IC(50) = 7.44 nM) yielded much improved hBuChE inhibitory activity compared to the lead A3Q12 (IC(50) = 63 nM). Besides, the selectivity indexes (SI = AChE IC(50) / BChE IC(50)) of 39 (SI = 33) and 43 (SI = 20) were also higher than A3Q12 (SI = 14). The results of the kinetic study showed that 39 and 43 exhibited a mixed-type inhibition against eqBuChE with respective K(i) values of 1.715 nM and 0.781 nM. And 39 and 43 could inhibit Abeta(1-42) peptide self-induced aggregation into fibril. X-ray crystallography structures of 39 or 43 complexes with BuChE revealed the molecular basis for their high potency. Thus, 39 and 43 are deserve for further study to develop potential drug candidates for the treatment of Alzheimer's disease.

Rapid discovery and crystallography study of highly potent and selective butylcholinesterase inhibitors based on oxime-containing libraries and conformational restriction strategies.,Jing L, Wei W, Meng B, Chantegreil F, Nachon F, Martinez A, Wu G, Zhao H, Song Y, Kang D, Brazzolotto X, Zhan P, Liu X Bioorg Chem. 2023 May;134:106465. doi: 10.1016/j.bioorg.2023.106465. Epub 2023 , Mar 11. PMID:36933339<ref>PMID:36933339</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7qhe" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Brazzolotto X]]
[[Category: Jing L]]
[[Category: Liu X]]
[[Category: Nachon F]]
[[Category: Zhan P]]