8ai7: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[8ai7]] 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=8AI7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AI7 FirstGlance]. <br>
<table><tr><td colspan='2'>[[8ai7]] 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=8AI7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AI7 FirstGlance]. <br>
</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=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=M8X:3-[[2-cycloheptylethyl(methyl)amino]methyl]-1~{H}-indol-7-ol'>M8X</scene>, <scene name='pdbligand=MKF:(2~{S})-2-azanyl-3-(dimethylcarbamoyloxy)propanoic+acid'>MKF</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
</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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=M8X:3-[[2-cycloheptylethyl(methyl)amino]methyl]-1~{H}-indol-7-ol'>M8X</scene>, <scene name='pdbligand=MKF:(2~{S})-2-azanyl-3-(dimethylcarbamoyloxy)propanoic+acid'>MKF</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=8ai7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ai7 OCA], [https://pdbe.org/8ai7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ai7 RCSB], [https://www.ebi.ac.uk/pdbsum/8ai7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ai7 ProSAT]</span></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=8ai7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ai7 OCA], [https://pdbe.org/8ai7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ai7 RCSB], [https://www.ebi.ac.uk/pdbsum/8ai7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ai7 ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
== 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>  
[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 ==
Alongside reversible butyrylcholinesterase inhibitors, a plethora of covalent butyrylcholinesterase inhibitors have been reported in the literature, typically pseudo-irreversible carbamates. For these latter, however, most cases lack full confirmation of their covalent mode of action. Additionally, the available reports regarding the structure-activity relationships of the O-arylcarbamate warhead are incomplete. Therefore, a follow-up on a series of pseudo-irreversible covalent carbamate human butyrylcholinesterase inhibitors and the structure-activity relationships of the N-dialkyl O-arylcarbamate warhead are presented in this study. The covalent mechanism of binding was tested by IC(50) time-dependency profiles, and sequentially and increasingly confirmed by kinetic analysis, whole protein LC-MS, and crystallographic analysis. Computational studies provided valuable insights into steric constraints and identified problematic, bulky carbamate warheads that cannot reach and carbamoylate the catalytic Ser198. Quantum mechanical calculations provided further evidence that steric effects appear to be a key factor in determining the covalent binding behaviour of these carbamate cholinesterase inhibitors and their duration of action. Additionally, the introduction of a clickable terminal alkyne moiety into one of the carbamate N-substituents and in situ derivatisation with azide-containing fluorophore enabled fluorescent labelling of plasma human butyrylcholinesterase. This proof-of-concept study highlights the potential of this novel approach and for these compounds to be further developed as clickable molecular probes for investigating tissue localisation and activity of cholinesterases.
Pseudo-irreversible butyrylcholinesterase inhibitors: Structure-activity relationships, computational and crystallographic study of the N-dialkyl O-arylcarbamate warhead.,Meden A, Knez D, Brazzolotto X, Modeste F, Perdih A, Pislar A, Zorman M, Zorovic M, Denic M, Pajk S, Zivin M, Nachon F, Gobec S Eur J Med Chem. 2023 Feb 5;247:115048. doi: 10.1016/j.ejmech.2022.115048. Epub , 2022 Dec 24. PMID:36586299<ref>PMID:36586299</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8ai7" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>

Latest revision as of 08:12, 7 February 2024

Structure of carbamoylated human butyrylcholinesterase upon reaction with 3-(((2-cycloheptylethyl)(methyl)amino)methyl)-1H-indol-7-yl N,N-dimethylcarbamate

8ai7, resolution 2.13Å

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