6rua: Difference between revisions
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The | ==Structure of recombinant human butyrylcholinesterase in complex with a coumarin-based fluorescent probe linked to sulfonamide type inhibitor.== | ||
<StructureSection load='6rua' size='340' side='right'caption='[[6rua]], [[Resolution|resolution]] 2.75Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6rua]] is a 2 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=6RUA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6RUA 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]] 2.75Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=KJT:diethyl-[6-[[2-[2-[2-[naphthalen-2-ylsulfonyl-[[(3~{R})-1-(phenylmethyl)piperidin-3-yl]methyl]amino]ethoxy]ethoxy]ethylamino]-oxidanyl-methyl]-7-oxidanylidene-1,3,4,4~{a},5,6,8,8~{a}-octahydronaphthalen-2-ylidene]azanium'>KJT</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</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=6rua FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rua OCA], [https://pdbe.org/6rua PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6rua RCSB], [https://www.ebi.ac.uk/pdbsum/6rua PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6rua 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 == | |||
Brain butyrylcholinesterase (BChE) is an attractive target for drugs designed for the treatment of Alzheimer's disease (AD) in its advanced stages. It also potentially represents a biomarker for progression of this disease. Based on the crystal structure of previously described highly potent, reversible, and selective BChE inhibitors, we have developed the fluorescent probes that are selective towards human BChE. The most promising probes also maintain their inhibition of BChE in the low nanomolar range with high selectivity over acetylcholinesterase. Kinetic studies of probes reveal a reversible mixed inhibition mechanism, with binding of these fluorescent probes to both the free and acylated enzyme. Probes show environment-sensitive emission, and additionally, one of them also shows significant enhancement of fluorescence intensity upon binding to the active site of BChE. Finally, the crystal structures of probes in complex with human BChE are reported, which offer an excellent base for further development of this library of compounds. | |||
Development of potent reversible selective inhibitors of butyrylcholinesterase as fluorescent probes.,Pajk S, Knez D, Kosak U, Zorovic M, Brazzolotto X, Coquelle N, Nachon F, Colletier JP, Zivin M, Stojan J, Gobec S J Enzyme Inhib Med Chem. 2020 Dec;35(1):498-505. doi:, 10.1080/14756366.2019.1710502. PMID:31914836<ref>PMID:31914836</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6rua" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: Coquelle | ==See Also== | ||
[[Category: | *[[Butyrylcholinesterase 3D structures|Butyrylcholinesterase 3D structures]] | ||
[[Category: | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Brus B]] | |||
[[Category: Colletier JP]] | |||
[[Category: Coquelle N]] | |||
[[Category: Gobec S]] | |||
[[Category: Knez D]] | |||
Latest revision as of 15:28, 24 January 2024
Structure of recombinant human butyrylcholinesterase in complex with a coumarin-based fluorescent probe linked to sulfonamide type inhibitor.Structure of recombinant human butyrylcholinesterase in complex with a coumarin-based fluorescent probe linked to sulfonamide type inhibitor.
Structural highlights
DiseaseCHLE_HUMAN Defects in BCHE are the cause of butyrylcholinesterase deficiency (BChE deficiency) [MIM: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. FunctionCHLE_HUMAN Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.[1] [2] Publication Abstract from PubMedBrain butyrylcholinesterase (BChE) is an attractive target for drugs designed for the treatment of Alzheimer's disease (AD) in its advanced stages. It also potentially represents a biomarker for progression of this disease. Based on the crystal structure of previously described highly potent, reversible, and selective BChE inhibitors, we have developed the fluorescent probes that are selective towards human BChE. The most promising probes also maintain their inhibition of BChE in the low nanomolar range with high selectivity over acetylcholinesterase. Kinetic studies of probes reveal a reversible mixed inhibition mechanism, with binding of these fluorescent probes to both the free and acylated enzyme. Probes show environment-sensitive emission, and additionally, one of them also shows significant enhancement of fluorescence intensity upon binding to the active site of BChE. Finally, the crystal structures of probes in complex with human BChE are reported, which offer an excellent base for further development of this library of compounds. Development of potent reversible selective inhibitors of butyrylcholinesterase as fluorescent probes.,Pajk S, Knez D, Kosak U, Zorovic M, Brazzolotto X, Coquelle N, Nachon F, Colletier JP, Zivin M, Stojan J, Gobec S J Enzyme Inhib Med Chem. 2020 Dec;35(1):498-505. doi:, 10.1080/14756366.2019.1710502. PMID:31914836[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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