4xii
From Proteopedia
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| - | ''' | + | ==X-ray structure of human butyrylcholinesteras win complex with 3-PYRIDIN-4-YL-2,4-DIHYDRO-INDENO[1,2-.C.]PYRAZOLE== |
| + | <StructureSection load='4xii' size='340' side='right' caption='[[4xii]], [[Resolution|resolution]] 2.70Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4xii]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XII OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XII FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=40V:N-{[(3R)-1-(2,3-DIHYDRO-1H-INDEN-2-YL)PIPERIDIN-3-YL]METHYL}-8-HYDROXY-N-(2-METHOXYETHYL)-5-NITROQUINOLINE-7-CARBOXAMIDE'>40V</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4tpk|4tpk]]</td></tr> | ||
| + | <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> | ||
| + | <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=4xii FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xii OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4xii RCSB], [http://www.ebi.ac.uk/pdbsum/4xii PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[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. | ||
| + | == Function == | ||
| + | [[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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Tremendous efforts have been dedicated to the development of effective therapeutics against Alzheimer's disease, which represents the most common debilitating neurodegenerative disease. Multifunctional agents are molecules designed to have simultaneous effects on different pathological processes. Such compounds represent an emerging strategy for the development of effective treatments against Alzheimer's disease. Here, we report on the synthesis and biological evaluation of a series of nitroxoline-based analogs that were designed by merging the scaffold of 8-hydroxyquinoline with that of a known selective butyrylcholinesterase inhibitor that has promising anti-Alzheimer properties. Most strikingly, compound 8g inhibits self-induced aggregation of the amyloid beta peptide (Abeta1-42), inhibits with sub-micromolar potency butyrylcholinesterase (IC50=215nM), and also selectively complexes Cu2+. Our study thus designates this compound as a promising multifunctional agent for therapeutic treatment of Alzheimer's disease. The crystal structure of human butyrylcholinesterase in complex with compound 8g is also solved, which suggests ways to further optimize compounds featuring the 8-hydroxyquinoline scaffold. | ||
| - | + | Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents.,Knez D, Brus B, Coquelle N, Sosic I, Sink R, Brazzolotto X, Mravljak J, Colletier JP, Gobec S Bioorg Med Chem. 2015 Jun 14. pii: S0968-0896(15)00504-0. doi:, 10.1016/j.bmc.2015.06.010. PMID:26116179<ref>PMID:26116179</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | == References == | |
| - | [[Category: | + | <references/> |
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Cholinesterase]] | ||
| + | [[Category: Boris, B]] | ||
| + | [[Category: Brazzolotto, X]] | ||
| + | [[Category: Colletier, J P]] | ||
[[Category: Coquelle, N]] | [[Category: Coquelle, N]] | ||
| - | [[Category: Boris, B]] | ||
[[Category: Gobec, S]] | [[Category: Gobec, S]] | ||
[[Category: Knez, D]] | [[Category: Knez, D]] | ||
| - | [[Category: | + | [[Category: Mravljak, J]] |
| - | + | ||
[[Category: Sink, R]] | [[Category: Sink, R]] | ||
| - | [[Category: Mravljak, J]] | ||
[[Category: Sosic, I]] | [[Category: Sosic, I]] | ||
| + | [[Category: Ab aggregation]] | ||
| + | [[Category: Abeta peptide]] | ||
| + | [[Category: Anti-alzherimer]] | ||
| + | [[Category: Hubuche]] | ||
| + | [[Category: Human butyrylcholinesterase]] | ||
| + | [[Category: Hydrolase]] | ||
| + | [[Category: Metal chelator]] | ||
Revision as of 14:47, 8 July 2015
X-ray structure of human butyrylcholinesteras win complex with 3-PYRIDIN-4-YL-2,4-DIHYDRO-INDENO[1,2-.C.]PYRAZOLE
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