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New page: left|200px<br /><applet load="1k4y" size="450" color="white" frame="true" align="right" spinBox="true" caption="1k4y, resolution 2.50Å" /> '''Crystal Structure of... |
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== | ==Crystal Structure of Rabbit Liver Carboxylesterase in Complex with 4-piperidino-piperidine== | ||
Mammalian carboxylesterases cleave the anticancer prodrug CPT-11 | <StructureSection load='1k4y' size='340' side='right'caption='[[1k4y]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[1k4y]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1K4Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1K4Y 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=4PN:4-PIPERIDINO-PIPERIDINE'>4PN</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=1k4y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1k4y OCA], [https://pdbe.org/1k4y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1k4y RCSB], [https://www.ebi.ac.uk/pdbsum/1k4y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1k4y ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/EST1_RABIT EST1_RABIT] Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs.<ref>PMID:9635592</ref> | |||
== 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/k4/1k4y_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=1k4y ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Mammalian carboxylesterases cleave the anticancer prodrug CPT-11 (Irinotecan) into SN-38, a potent topoisomerase I poison, and 4-piperidino-piperidine (4PP). We present the 2.5 A crystal structure of rabbit liver carboxylesterase (rCE), the most efficient enzyme known to activate CPT-11 in this manner, in complex with the leaving group 4PP. 4PP is observed bound adjacent to a high-mannose Asn-linked glycosylation site on the surface of rCE. This product-binding site is separated from the catalytic gorge by a thin wall of amino acid side chains, suggesting that 4PP may be released through this secondary product exit pore. The crystallographic observation of a leaving group bound on the surface of rCE supports the 'back door' product exit site proposed for the acetylcholinesterases. These results may facilitate the design of improved anticancer drugs or enzymes for use in viral-directed cancer cotherapies. | |||
Structural insights into CPT-11 activation by mammalian carboxylesterases.,Bencharit S, Morton CL, Howard-Williams EL, Danks MK, Potter PM, Redinbo MR Nat Struct Biol. 2002 May;9(5):337-42. PMID:11967565<ref>PMID:11967565</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
[[Category: | <div class="pdbe-citations 1k4y" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Carboxylesterase 3D structures|Carboxylesterase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Oryctolagus cuniculus]] | [[Category: Oryctolagus cuniculus]] | ||
[[Category: Bencharit S]] | |||
[[Category: Bencharit | [[Category: Danks MK]] | ||
[[Category: Danks | [[Category: Howard-Williams EL]] | ||
[[Category: Howard-Williams | [[Category: Morton CL]] | ||
[[Category: Morton | [[Category: Potter PM]] | ||
[[Category: Potter | [[Category: Redinbo MR]] | ||
[[Category: Redinbo | |||
Latest revision as of 10:20, 9 October 2024
Crystal Structure of Rabbit Liver Carboxylesterase in Complex with 4-piperidino-piperidineCrystal Structure of Rabbit Liver Carboxylesterase in Complex with 4-piperidino-piperidine
Structural highlights
FunctionEST1_RABIT Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs.[1] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedMammalian carboxylesterases cleave the anticancer prodrug CPT-11 (Irinotecan) into SN-38, a potent topoisomerase I poison, and 4-piperidino-piperidine (4PP). We present the 2.5 A crystal structure of rabbit liver carboxylesterase (rCE), the most efficient enzyme known to activate CPT-11 in this manner, in complex with the leaving group 4PP. 4PP is observed bound adjacent to a high-mannose Asn-linked glycosylation site on the surface of rCE. This product-binding site is separated from the catalytic gorge by a thin wall of amino acid side chains, suggesting that 4PP may be released through this secondary product exit pore. The crystallographic observation of a leaving group bound on the surface of rCE supports the 'back door' product exit site proposed for the acetylcholinesterases. These results may facilitate the design of improved anticancer drugs or enzymes for use in viral-directed cancer cotherapies. Structural insights into CPT-11 activation by mammalian carboxylesterases.,Bencharit S, Morton CL, Howard-Williams EL, Danks MK, Potter PM, Redinbo MR Nat Struct Biol. 2002 May;9(5):337-42. PMID:11967565[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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