View source for 1eve

==THREE DIMENSIONAL STRUCTURE OF THE ANTI-ALZHEIMER DRUG, E2020 (ARICEPT), COMPLEXED WITH ITS TARGET ACETYLCHOLINESTERASE==
<StructureSection load='' size='340' side='right' caption='[[1eve]], [[Resolution|resolution]] 2.50&Aring;' scene='76/761810/E2020/1'>
== Structural highlights ==
<table><tr><td colspan='2'>[[1eve]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Torpedo_californica Torpedo californica]. The June 2004 RCSB PDB [http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Acetylcholinesterase''  by David S. Goodsell is [http://dx.doi.org/10.2210/rcsb_pdb/mom_2004_6 10.2210/rcsb_pdb/mom_2004_6]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EVE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1EVE FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=E20:1-BENZYL-4-[(5,6-DIMETHOXY-1-INDANON-2-YL)METHYL]PIPERIDINE'>E20</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Acetylcholinesterase Acetylcholinesterase], with EC number [http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1eve FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1eve OCA], [http://pdbe.org/1eve PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1eve RCSB], [http://www.ebi.ac.uk/pdbsum/1eve PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1eve ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/ACES_TORCA ACES_TORCA]] Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. May be involved in cell-cell interactions. 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ev/1eve_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1eve ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
BACKGROUND: Several cholinesterase inhibitors are either being utilized for symptomatic treatment of Alzheimer's disease or are in advanced clinical trials. E2020, marketed as Aricept, is a member of a large family of N-benzylpiperidine-based acetylcholinesterase (AChE) inhibitors developed, synthesized and evaluated by the Eisai Company in Japan. These inhibitors were designed on the basis of QSAR studies, prior to elucidation of the three-dimensional structure of Torpedo californica AChE (TcAChE). It significantly enhances performance in animal models of cholinergic hypofunction and has a high affinity for AChE, binding to both electric eel and mouse AChE in the nanomolar range. RESULTS: Our experimental structure of the E2020-TcAChE complex pinpoints specific interactions responsible for the high affinity and selectivity demonstrated previously. It shows that E2020 has a unique orientation along the active-site gorge, extending from the anionic subsite of the active site, at the bottom, to the peripheral anionic site, at the top, via aromatic stacking interactions with conserved aromatic acid residues. E2020 does not, however, interact directly with either the catalytic triad or the 'oxyanion hole', but only indirectly via solvent molecules. CONCLUSIONS: Our study shows, a posteriori, that the design of E2020 took advantage of several important features of the active-site gorge of AChE to produce a drug with both high affinity for AChE and a high degree of selectivity for AChE versus butyrylcholinesterase (BChE). It also delineates voids within the gorge that are not occupied by E2020 and could provide sites for potential modification of E2020 to produce drugs with improved pharmacological profiles.

Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs.,Kryger G, Silman I, Sussman JL Structure. 1999 Mar 15;7(3):297-307. PMID:10368299<ref>PMID:10368299</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1eve" style="background-color:#fffaf0;"></div>

==See Also==
*[[AChE inhibitors and substrates|AChE inhibitors and substrates]]
*[[Acetylcholinesterase 3D structures|Acetylcholinesterase 3D structures]]
*[[Acetylcholinesterase: Treatment of Alzheimer's disease|Acetylcholinesterase: Treatment of Alzheimer's disease]]
*[[Aricept Complexed with Acetylcholinesterase|Aricept Complexed with Acetylcholinesterase]]
*[[Huperzine A Complexed with Acetylcholinesterase|Huperzine A Complexed with Acetylcholinesterase]]
*[[Joel Sussman's Favorites|Joel Sussman's Favorites]]
*[[Site|Site]]
*[[User:Wayne Decatur/Chem791A Work Session|User:Wayne Decatur/Chem791A Work Session]]
*[[User:Wayne Decatur/Teaching Proteopedia|User:Wayne Decatur/Teaching Proteopedia]]
*[[3D structures of acetylcholinesterase|3D structures of acetylcholinesterase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Acetylcholinesterase]]
[[Category: RCSB PDB Molecule of the Month]]
[[Category: Torpedo californica]]
[[Category: Kryger, G]]
[[Category: Silman, I]]
[[Category: Sussman, J L]]
[[Category: Alpha/beta hydrolase]]
[[Category: Alzheimer's disease]]
[[Category: Catalytic triad]]
[[Category: Drug]]
[[Category: Glycosylated protein]]
[[Category: Neurotransmitter cleavage]]
[[Category: Serine hydrolase]]