View source for 4a23


==Mus musculus Acetylcholinesterase in complex with racemic C5685==
<StructureSection load='4a23' size='340' side='right'caption='[[4a23]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4a23]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4A23 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4A23 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C56:4-(DIMETHYLAMINO)-N-{[(2R)-1-ETHYLPYRROLIDIN-2-YL]METHYL}-2-METHOXY-5-NITROBENZAMIDE'>C56</scene>, <scene name='pdbligand=C57:4-(DIMETHYLAMINO)-N-{[(2S)-1-ETHYLPYRROLIDIN-2-YL]METHYL}-2-METHOXY-5-NITROBENZAMIDE'>C57</scene>, <scene name='pdbligand=PE4:2-{2-[2-(2-{2-[2-(2-ETHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL'>PE4</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2jgh|2jgh]], [[2whq|2whq]], [[1mah|1mah]], [[1maa|1maa]], [[2ha6|2ha6]], [[2c0q|2c0q]], [[2jgg|2jgg]], [[2jgl|2jgl]], [[2xug|2xug]], [[1q84|1q84]], [[2xud|2xud]], [[2jgm|2jgm]], [[2xuj|2xuj]], [[2jge|2jge]], [[1q83|1q83]], [[2wls|2wls]], [[2xup|2xup]], [[2xuk|2xuk]], [[1c2b|1c2b]], [[2y2u|2y2u]], [[2ha3|2ha3]], [[2ha0|2ha0]], [[2wu3|2wu3]], [[2xuf|2xuf]], [[2jey|2jey]], [[2jgi|2jgi]], [[1n5r|1n5r]], [[2xuh|2xuh]], [[2jgj|2jgj]], [[1j06|1j06]], [[2c0p|2c0p]], [[2jf0|2jf0]], [[2xuo|2xuo]], [[2h9y|2h9y]], [[2whr|2whr]], [[2xui|2xui]], [[1n5m|1n5m]], [[2ha5|2ha5]], [[2ha2|2ha2]], [[2xuq|2xuq]], [[2whp|2whp]], [[2jez|2jez]], [[2jgk|2jgk]], [[1ku6|1ku6]], [[2ha4|2ha4]], [[1j07|1j07]], [[2ha7|2ha7]], [[2jgf|2jgf]], [[2y2v|2y2v]], [[2wu4|2wu4]], [[1c2o|1c2o]], [[4a16|4a16]]</div></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Acetylcholinesterase Acetylcholinesterase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.7 3.1.1.7] </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=4a23 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4a23 OCA], [https://pdbe.org/4a23 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4a23 RCSB], [https://www.ebi.ac.uk/pdbsum/4a23 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4a23 ProSAT]</span></td></tr>
</table>
== Function ==
[[https://www.uniprot.org/uniprot/ACES_MOUSE ACES_MOUSE]] Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Acetylcholinesterase (AChE) is an essential enzyme that terminates cholinergic transmission by rapid hydrolysis of the neurotransmitter acetylcholine. Compounds inhibiting this enzyme can be used (inter alia) to treat cholinergic deficiencies (e.g. in Alzheimer's disease), but may also act as dangerous toxins (e.g. nerve agents such as sarin). Treatment of nerve agent poisoning involves use of antidotes, small molecules capable of reactivating AChE. We have screened a collection of organic molecules to assess their ability to inhibit the enzymatic activity of AChE, aiming to find lead compounds for further optimization leading to drugs with increased efficacy and/or decreased side effects. 124 inhibitors were discovered, with considerable chemical diversity regarding size, polarity, flexibility and charge distribution. An extensive structure determination campaign resulted in a set of crystal structures of protein-ligand complexes. Overall, the ligands have substantial interactions with the peripheral anionic site of AChE, and the majority form additional interactions with the catalytic site (CAS). Reproduction of the bioactive conformation of six of the ligands using molecular docking simulations required modification of the default parameter settings of the docking software. The results show that docking-assisted structure-based design of AChE inhibitors is challenging and requires crystallographic support to obtain reliable results, at least with currently available software. The complex formed between C5685 and Mus musculus AChE (C5685*mAChE) is a representative structure for the general binding mode of the determined structures. The CAS binding part of C5685 could not be structurally determined due to a disordered electron density map and the developed docking protocol was used to predict the binding modes of this part of the molecule. We believe that chemical modifications of our discovered inhibitors, biochemical and biophysical characterization, crystallography and computational chemistry provide a route to novel AChE inhibitors and reactivators.

Targeting acetylcholinesterase: identification of chemical leads by high throughput screening, structure determination and molecular modeling.,Berg L, Andersson CD, Artursson E, Hornberg A, Tunemalm AK, Linusson A, Ekstrom F PLoS One. 2011;6(11):e26039. Epub 2011 Nov 30. PMID:22140425<ref>PMID:22140425</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4a23" style="background-color:#fffaf0;"></div>

==See Also==
*[[Acetylcholinesterase 3D structures|Acetylcholinesterase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Acetylcholinesterase]]
[[Category: Large Structures]]
[[Category: Lk3 transgenic mice]]
[[Category: Andersson, C D]]
[[Category: Artrursson, E]]
[[Category: Berg, L]]
[[Category: Ekstrom, F]]
[[Category: Hornberg, A]]
[[Category: Linusson, A]]
[[Category: Tunemalm, A K]]
[[Category: Cholinesterase]]
[[Category: Hydrolase]]