View source for 7qbr


==Human butyrylcholinesterase in complex with (Z)-N-tert-butyl-1-(8-(3-(4-(prop-2-yn-1-yl)piperazin-1-yl)propoxy)quinolin-2-yl)methanimine oxide==
<StructureSection load='7qbr' size='340' side='right'caption='[[7qbr]], [[Resolution|resolution]] 2.13&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7qbr]] 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=7QBR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QBR 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]] 2.13&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AI6:~{N}-~{tert}-butyl-1-[8-[3-(4-prop-2-ynylpiperazin-1-yl)propoxy]quinolin-2-yl]methanimine+oxide'>AI6</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=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=7qbr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qbr OCA], [https://pdbe.org/7qbr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qbr RCSB], [https://www.ebi.ac.uk/pdbsum/7qbr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qbr 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 ==
We describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesterase-hBChE) and monoamine oxidases (hMAO-A/B) for the therapy of neurodegenerative diseases. We identified QN 19, a simple, low molecular weight nitrone, that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde. Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition, yet unexpectedly showed potent inhibition of hBChE (IC(50) = 1.06 +/- 0.31 nmol/L) and hMAO-B (IC(50) = 4.46 +/- 0.18 mumol/L). The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding, which was further studied by enzyme kinetics. Compound 19 acted as a free radical scavenger and biometal chelator, crossed the blood-brain barrier, was not cytotoxic, and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease. In addition, in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination. Importantly, chronic treatment of double transgenic APPswe-PS1deltaE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice, underscoring the disease-modifying effect of QN 19.

8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases.,Knez D, Diez-Iriepa D, Chioua M, Gottinger A, Denic M, Chantegreil F, Nachon F, Brazzolotto X, Skrzypczak-Wiercioch A, Meden A, Pislar A, Kos J, Zakelj S, Stojan J, Salat K, Serrano J, Fernandez AP, Sanchez-Garcia A, Martinez-Murillo R, Binda C, Lopez-Munoz F, Gobec S, Marco-Contelles J Acta Pharm Sin B. 2023 May;13(5):2152-2175. doi: 10.1016/j.apsb.2023.01.013. Epub , 2023 Jan 19. PMID:37250172<ref>PMID:37250172</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7qbr" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Brazzolotto X]]
[[Category: Chioua M]]
[[Category: Denic M]]
[[Category: Gobec S]]
[[Category: Knez D]]
[[Category: Marco-Contelles JL]]
[[Category: Nachon F]]