9ewu
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of human butyrylcholinesterase in complex with (2R,3S)-1-[(cyclopropylmethyl)amino]-3-[(9H-fluoren-9-yl)amino]-4-phenylbutan-2-ol== | |
| + | <StructureSection load='9ewu' size='340' side='right'caption='[[9ewu]], [[Resolution|resolution]] 2.45Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9ewu]] 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=9EWU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9EWU 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]] 2.45Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1H77:(2~{R},3~{S})-1-(cyclopropylmethylamino)-3-(9~{H}-fluoren-9-ylamino)-4-phenyl-butan-2-ol'>A1H77</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=9ewu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9ewu OCA], [https://pdbe.org/9ewu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9ewu RCSB], [https://www.ebi.ac.uk/pdbsum/9ewu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9ewu 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 == | ||
| + | Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and behavioral and psychological symptoms of dementia (BPSD). Given that cholinergic neurons are predominantly affected in AD, current treatments primarily aim to enhance cholinergic neurotransmission. However, imbalances in other neurotransmitters, such as gamma-aminobutyric acid (GABA), also contribute to AD symptomatology. In the presented research, using a combination of crystallography and computational methods we developed compound 6 as a dual modulator of GABAergic and cholinergic neurotransmission systems. Compound 6 demonstrated inhibition of BuChE (IC(50)=0.21 muM) and GABA transporter 1 (IC(50)=10.96 muM) and 3 (IC(50)=7.76 muM), along with a favorable drug-likeness profile. Subsequent in vivo studies revealed the effectiveness of 6 in enhancing memory retention and alleviating anxiety and depression symptoms in animal models, while also proving safe and bioavailable for oral administration. The innovative multi-target-directed ligand 6 offers a new approach to treating cognitive deficits and BPSD in AD. | ||
| - | + | Multifunctional, Fluorene-Based Modulator of Cholinergic and GABAergic Neurotransmission as a Novel Drug Candidate for Palliative Treatment of Alzheimer's Disease.,Panek D, Pasieka A, Jonczyk J, Gawlinska M, Zareba P, Siwek A, Wolak M, Mordyl B, Gluch-Lutwin M, Latacz G, Brazzolotto X, Chantegreil F, Nachon F, Zdarova Karasova J, Pejchal J, Mzik M, Sestak V, Prchal L, Odvarkova J, Soukup O, Korabecny J, Sorf A, Hamsikova M, Zemanova L, Muckova L, Vanova N, Dryja P, Salat K, Hofner G, Wanner K, Wieckowska A, Malawska B Angew Chem Int Ed Engl. 2024 Nov 11:e202420510. doi: 10.1002/anie.202420510. PMID:39523866<ref>PMID:39523866</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 9ewu" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Brazzolotto X]] | ||
| + | [[Category: Malawska B]] | ||
| + | [[Category: Nachon F]] | ||
| + | [[Category: Panek D]] | ||
| + | [[Category: Pasieka A]] | ||
Current revision
Crystal structure of human butyrylcholinesterase in complex with (2R,3S)-1-[(cyclopropylmethyl)amino]-3-[(9H-fluoren-9-yl)amino]-4-phenylbutan-2-ol
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