1u65

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{{STRUCTURE_1u65| PDB=1u65 | SCENE= }}
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==Ache W. CPT-11==
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===Ache W. CPT-11===
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<StructureSection load='1u65' size='340' side='right' caption='[[1u65]], [[Resolution|resolution]] 2.61&Aring;' scene=''>
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{{ABSTRACT_PUBMED_15772291}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1u65]] 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=1U65 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1U65 FirstGlance]. <br>
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</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CP0:(4S)-4,11-DIETHYL-4-HYDROXY-3,14-DIOXO-3,4,12,14-TETRAHYDRO-1H-PYRANO[3,4 6,7]INDOLIZINO[1,2-B]QUINOLIN-9-YL+1,4-BIPIPERIDINE-1-CARBOXYLATE'>CP0</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=FUL:BETA-L-FUCOSE'>FUL</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NDG:2-(ACETYLAMINO)-2-DEOXY-A-D-GLUCOPYRANOSE'>NDG</scene><br>
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<tr><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>
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<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1u65 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1u65 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1u65 RCSB], [http://www.ebi.ac.uk/pdbsum/1u65 PDBsum], [http://www.topsan.org/Proteins/ISPC/1u65 TOPSAN]</span></td></tr>
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<table>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/u6/1u65_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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/chain_selection.php?pdb_ID=2ata ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The anticancer prodrug 7-ethyl-10-[4-(1-piperidino)-1-piperidino-]carbonyloxycamptothecin (CPT-11) is a highly effective camptothecin analog that has been approved for the treatment of colon cancer. It is hydrolyzed by carboxylesterases to yield 7-ethyl-10-hydroxycamptothecin (SN-38), a potent topoisomerase I poison. However, upon high-dose intravenous administration of CPT-11, a cholinergic syndrome is observed that can be ameliorated by atropine. Previous studies have indicated that CPT-11 can inhibit acetylcholinesterase (AChE), and here, we provide a detailed analysis of the inhibition of AChE by CPT-11 and by structural analogs. These studies demonstrate that the terminal dipiperidino moiety in CPT-11 plays a major role in enzyme inhibition, and this has been confirmed by X-ray crystallographic studies of a complex of the drug with Torpedo californica AChE. Our results indicate that CPT-11 binds within the active site gorge of the protein in a fashion similar to that observed with the Alzheimer drug donepezil. The 3D structure of the CPT-11/AChE complex also permits modeling of CPT-11 complexed with mammalian butyrylcholinesterase and carboxylesterase, both of which are known to hydrolyze the drug to the active metabolite. Overall, the results presented here clarify the mechanism of AChE inhibition by CPT-11 and detail the interaction of the drug with the protein. These studies may allow the design of both novel camptothecin analogs that would not inhibit AChE and new AChE inhibitors derived from the camptothecin scaffold.
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==About this Structure==
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The crystal structure of the complex of the anticancer prodrug 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11) with Torpedo californica acetylcholinesterase provides a molecular explanation for its cholinergic action.,Harel M, Hyatt JL, Brumshtein B, Morton CL, Yoon KJ, Wadkins RM, Silman I, Sussman JL, Potter PM Mol Pharmacol. 2005 Jun;67(6):1874-81. Epub 2005 Mar 16. PMID:15772291<ref>PMID:15772291</ref>
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[[1u65]] 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=1U65 OCA].
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
==See Also==
==See Also==
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*[[Acetylcholinesterase|Acetylcholinesterase]]
*[[Acetylcholinesterase|Acetylcholinesterase]]
*[[User:Boris Brumshtein|User:Boris Brumshtein]]
*[[User:Boris Brumshtein|User:Boris Brumshtein]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:015772291</ref><references group="xtra"/>
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__TOC__
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</StructureSection>
[[Category: Acetylcholinesterase]]
[[Category: Acetylcholinesterase]]
[[Category: Torpedo californica]]
[[Category: Torpedo californica]]

Revision as of 19:05, 29 September 2014

Ache W. CPT-11

1u65, resolution 2.61Å

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