3arn: Difference between revisions
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==Human dUTPase in complex with novel uracil derivative== | ==Human dUTPase in complex with novel uracil derivative== | ||
<StructureSection load='3arn' size='340' side='right' caption='[[3arn]], [[Resolution|resolution]] 1.80Å' scene=''> | <StructureSection load='3arn' size='340' side='right' caption='[[3arn]], [[Resolution|resolution]] 1.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3arn]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[3arn]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ARN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ARN FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MSJ:N-{5-[(2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-1(2H)-YL)METHOXY]-2-METHYLPENTAN-2-YL}BENZENESULFONAMIDE'>MSJ</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MSJ:N-{5-[(2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-1(2H)-YL)METHOXY]-2-METHYLPENTAN-2-YL}BENZENESULFONAMIDE'>MSJ</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ara|3ara]], [[2hqu|2hqu]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ara|3ara]], [[2hqu|2hqu]]</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/dUTP_diphosphatase dUTP diphosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.1.23 3.6.1.23] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/dUTP_diphosphatase dUTP diphosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.1.23 3.6.1.23] </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=3arn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3arn OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3arn RCSB], [http://www.ebi.ac.uk/pdbsum/3arn PDBsum]</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=3arn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3arn OCA], [http://pdbe.org/3arn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3arn RCSB], [http://www.ebi.ac.uk/pdbsum/3arn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3arn ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 3arn" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Human]] | ||
[[Category: DUTP diphosphatase]] | [[Category: DUTP diphosphatase]] | ||
[[Category: Chong, K T]] | [[Category: Chong, K T]] | ||
Revision as of 16:22, 5 August 2016
Human dUTPase in complex with novel uracil derivativeHuman dUTPase in complex with novel uracil derivative
Structural highlights
Function[DUT_HUMAN] This enzyme is involved in nucleotide metabolism: it produces dUMP, the immediate precursor of thymidine nucleotides and it decreases the intracellular concentration of dUTP so that uracil cannot be incorporated into DNA.[1] Publication Abstract from PubMedInhibition of human deoxyuridine triphosphatase (dUTPase) has been identified as a promising approach to enhance the efficacy of 5-fluorouracil (5-FU)-based chemotherapy. This study describes the development of a novel class of dUTPase inhibitors based on the structure-activity relationship (SAR) studies of uracil derivatives. Starting from the weak inhibitor 7 (IC(50) = 100 muM), we developed compound 26, which is the most potent human dUTPase inhibitor (IC(50) = 0.021 muM) reported to date. Not only does compound 26 significantly enhance the growth inhibition activity of 5-fluoro-2'-deoxyuridine (FdUrd) against HeLa S3 cells in vitro (EC(50) = 0.075 muM) but also shows robust antitumor activity against MX-1 breast cancer xenograft model in mice when administered orally with a continuous infusion of 5-FU. This is the first in vivo evidence that human dUTPase inhibitors enhance the antitumor activity of TS inhibitors. On the basis of these findings, it was concluded that compound 26 is a promising candidate for clinical development. Discovery of a novel class of potent human deoxyuridine triphosphatase inhibitors remarkably enhancing the antitumor activity of thymidylate synthase inhibitors.,Miyahara S, Miyakoshi H, Yokogawa T, Chong KT, Taguchi J, Muto T, Endoh K, Yano W, Wakasa T, Ueno H, Takao Y, Fujioka A, Hashimoto A, Itou K, Yamamura K, Nomura M, Nagasawa H, Shuto S, Fukuoka M J Med Chem. 2012 Apr 12;55(7):2970-80. Epub 2012 Mar 26. PMID:22339362[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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