View source for 1h23

==Structure of acetylcholinesterase (E.C. 3.1.1.7) complexed with (S,S)-(-)-bis(12)-hupyridone at 2.15A resolution==
<StructureSection load='1h23' size='340' side='right' caption='[[1h23]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1h23]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Torpedo_californica Torpedo californica]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1H23 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1H23 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=E12:(S,S)-(-)-N,N-DI-5-[5,6,7,8-TETRAHYDRO-+2(1H)-QUINOLYNYL]-1,12-DIAMINODODECANE+DIHYDROCHLORIDE'>E12</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1acj|1acj]], [[1acl|1acl]], [[1amn|1amn]], [[1ax9|1ax9]], [[1cfj|1cfj]], [[1dx6|1dx6]], [[1e3q|1e3q]], [[1e66|1e66]], [[1ea5|1ea5]], [[1eea|1eea]], [[1eve|1eve]], [[1fss|1fss]], [[1gpk|1gpk]], [[1gpn|1gpn]], [[1gqr|1gqr]], [[1gqs|1gqs]], [[1hbj|1hbj]], [[1h22|1h22]], [[1jjb|1jjb]], [[1oce|1oce]], [[1qid|1qid]], [[1qie|1qie]], [[1qif|1qif]], [[1qig|1qig]], [[1qih|1qih]], [[1qii|1qii]], [[1qij|1qij]], [[1qik|1qik]], [[1qim|1qim]], [[1qti|1qti]], [[1som|1som]], [[1vot|1vot]], [[1vxo|1vxo]], [[1vxr|1vxr]], [[2ace|2ace]], [[2ack|2ack]], [[2dfp|2dfp]], [[3ace|3ace]], [[4ace|4ace]]</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=1h23 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h23 OCA], [http://pdbe.org/1h23 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1h23 RCSB], [http://www.ebi.ac.uk/pdbsum/1h23 PDBsum]</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/h2/1h23_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=1h23 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Acetylcholinesterase (AChE) inhibitors improve the cognitive abilities of Alzheimer patients. (-)-Huperzine A [(-)-HupA], an alkaloid isolated from the club moss, Huperzia serrata, is one such inhibitor, but the search for more potent and selective drugs continues. Recently, alkylene-linked dimers of 5-amino-5,6,7,8-tetrahydroquinolinone (hupyridone, 1a), a fragment of HupA, were shown to serve as more potent inhibitors of AChE than (-)-HupA and monomeric 1a. We soaked two such dimers, (S,S)-(-)-bis(10)-hupyridone [(S,S)-(-)-2a] and (S,S)-(-)-bis(12)-hupyridone [(S,S)-(-)-2b] containing, respectively, 10 and 12 methylenes in the spacer, into trigonal TcAChE crystals, and solved the X-ray structures of the resulting complexes using the difference Fourier technique, both to 2.15 A resolution. The structures revealed one HupA-like 1a unit bound to the "anionic" subsite of the active-site, near the bottom of the active-site gorge, adjacent to Trp84, as seen for the TcAChE/(-)-HupA complex, and the second 1a unit near Trp279 in the "peripheral" anionic site at the top of the gorge, both bivalent molecules thus spanning the active-site gorge. The results confirm that the increased affinity of the dimeric HupA analogues for AChE is conferred by binding to the two "anionic" sites of the enzyme. Inhibition data show that (-)-2a binds to TcAChE approximately 6-7- and &gt; 170-fold more tightly than (-)-2b and (-)-HupA, respectively. In contrast, previous data for rat AChE show that (-)-2b binds approximately 3- and approximately 2-fold more tightly than (-)-2a and (-)-HupA, respectively. Structural comparison of TcAChE with rat AChE, as represented by the closely related mouse AChE structure (1maa.pdb), reveals a narrower gorge for rat AChE, a perpendicular alignment of the Tyr337 ring to the gorge axis, and its conformational rigidity, as a result of hydrogen bonding between its hydroxyl group and that of Tyr341, relative to TcAChE Phe330. These structural differences in the active-site gorge explain the switch in inhibitory potency of (-)-2a and 2b and the larger dimer/(-)-HupA potency ratios observed for TcAChE relative to rat AChE. The results offer new insights into factors affecting protein-ligand complementarity within the gorge and should assist the further development of improved AChE inhibitors.

Acetylcholinesterase complexed with bivalent ligands related to huperzine a: experimental evidence for species-dependent protein-ligand complementarity.,Wong DM, Greenblatt HM, Dvir H, Carlier PR, Han YF, Pang YP, Silman I, Sussman JL J Am Chem Soc. 2003 Jan 15;125(2):363-73. PMID:12517147<ref>PMID:12517147</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1h23" style="background-color:#fffaf0;"></div>

==See Also==
*[[AChE inhibitors and substrates|AChE inhibitors and substrates]]
*[[Torpedo Californica Acetylcholinesterase in complex with an (R)-Tacrine-(10)-Hupyridone inhibitor|Torpedo Californica Acetylcholinesterase in complex with an (R)-Tacrine-(10)-Hupyridone inhibitor]]
*[[User:Dawn M. Wong|User:Dawn M. Wong]]
*[[3D structures of acetylcholinesterase|3D structures of acetylcholinesterase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Acetylcholinesterase]]
[[Category: Torpedo californica]]
[[Category: Carlier, P R]]
[[Category: Greenblatt, H M]]
[[Category: Han, Y F]]
[[Category: Pang, Y P]]
[[Category: Silman, I]]
[[Category: Sussman, J L]]
[[Category: Wong, D M]]
[[Category: Alzheimer's disease]]
[[Category: Bivalent ligand]]
[[Category: Dual-site binding]]
[[Category: Glycoprotein]]
[[Category: Gpi-anchor neurotransmitter degradation]]
[[Category: Huperzine some]]
[[Category: Hydrolase]]
[[Category: Inhibitor]]
[[Category: Membrane]]
[[Category: Muscle]]
[[Category: Nerve]]
[[Category: Neurotransmitter cleavage]]
[[Category: Serine esterase synapse]]
[[Category: Serine hydrolase]]