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== | ==X-ray Crystal structure of complex between Torpedo californica AChE and a reversible inhibitor, 4-Amino-5-fluoro-2-methyl-3-(3-trifluoroacetylbenzylthiomethyl)quinoline== | ||
[[http://www.uniprot.org/uniprot/ | <StructureSection load='1hbj' size='340' side='right'caption='[[1hbj]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[1hbj]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Tetronarce_californica Tetronarce californica]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1HBJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1HBJ 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]] 2.5Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FBQ:1-[3-({[(4-AMINO-5-FLUORO-2-METHYLQUINOLIN-3-YL)METHYL]THIO}METHYL)PHENYL]-2,2,2-TRIFLUOROETHANE-1,1-DIOL'>FBQ</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</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=1hbj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1hbj OCA], [https://pdbe.org/1hbj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1hbj RCSB], [https://www.ebi.ac.uk/pdbsum/1hbj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1hbj ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/ACES_TETCF ACES_TETCF] 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/hb/1hbj_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=1hbj ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Chimeras of tacrine and m-(N,N,N-Trimethylammonio)trifluoroacetophenone (1) were designed as novel, reversible inhibitors of acetylcholinesterase. On the basis of the X-ray structure of the apoenzyme, a molecular modeling study determined the favored attachment positions on the 4-aminoquinoline ring (position 3 and the 4-amino nitrogen) and the favored lengths of a polymethylene link between the two moieties (respectively 5-6 and 4-5 sp(3) atoms). Seven compounds matching these criteria were synthesized, and their inhibitory potencies were determined to be in the low nanomolar range. Activity data for close analogues lacking some of the postulated key features showed that our predictions were correct. In addition, a subsequent crystal structure of acetylcholinesterase complexed with the most active compound 27 was in good agreement with our model. The design strategy is therefore validated and can now be developed further. | |||
A structure-based design approach to the development of novel, reversible AChE inhibitors.,Doucet-Personeni C, Bentley PD, Fletcher RJ, Kinkaid A, Kryger G, Pirard B, Taylor A, Taylor R, Taylor J, Viner R, Silman I, Sussman JL, Greenblatt HM, Lewis T J Med Chem. 2001 Sep 27;44(20):3203-15. PMID:11563919<ref>PMID:11563919</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
< | </div> | ||
[[Category: | <div class="pdbe-citations 1hbj" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: Doucet | ==See Also== | ||
[[Category: Greenblatt | *[[Acetylcholinesterase 3D structures|Acetylcholinesterase 3D structures]] | ||
[[Category: Kryger | == References == | ||
[[Category: Lewis | <references/> | ||
[[Category: Silman | __TOC__ | ||
[[Category: Sussman | </StructureSection> | ||
[[Category: Viner | [[Category: Large Structures]] | ||
[[Category: Tetronarce californica]] | |||
[[Category: Doucet C]] | |||
[[Category: Greenblatt HM]] | |||
[[Category: Kryger G]] | |||
[[Category: Lewis TL]] | |||
[[Category: Silman I]] | |||
[[Category: Sussman JL]] | |||
[[Category: Viner R]] | |||