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| | ==Tdt core in complex with inhibitor (2Z,5E)-6-[4-(4-fluorobenzoyl)-1H-pyrrol-2-yl]-2-hydroxy-4-oxohexa-2,5-dienoic acid== | | ==Tdt core in complex with inhibitor (2Z,5E)-6-[4-(4-fluorobenzoyl)-1H-pyrrol-2-yl]-2-hydroxy-4-oxohexa-2,5-dienoic acid== |
| - | <StructureSection load='4iqu' size='340' side='right' caption='[[4iqu]], [[Resolution|resolution]] 2.40Å' scene=''> | + | <StructureSection load='4iqu' size='340' side='right'caption='[[4iqu]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4iqu]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IQU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4IQU FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4iqu]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IQU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IQU FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1FQ:(2Z,5E)-6-[4-(4-FLUOROBENZOYL)-1H-PYRROL-2-YL]-2-HYDROXY-4-OXOHEXA-2,5-DIENOIC+ACID'>1FQ</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1FQ:(2Z,5E)-6-[4-(4-FLUOROBENZOYL)-1H-PYRROL-2-YL]-2-HYDROXY-4-OXOHEXA-2,5-DIENOIC+ACID'>1FQ</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4iqt|4iqt]], [[4iqv|4iqv]], [[4iqw|4iqw]]</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=4iqu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4iqu OCA], [https://pdbe.org/4iqu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4iqu RCSB], [https://www.ebi.ac.uk/pdbsum/4iqu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4iqu ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Dntt, Tdt ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA_nucleotidylexotransferase DNA nucleotidylexotransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.31 2.7.7.31] </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=4iqu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4iqu OCA], [http://pdbe.org/4iqu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4iqu RCSB], [http://www.ebi.ac.uk/pdbsum/4iqu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4iqu ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/TDT_MOUSE TDT_MOUSE]] Template-independent DNA polymerase which catalyzes the random addition of deoxynucleoside 5'-triphosphate to the 3'-end of a DNA initiator. One of the in vivo functions of this enzyme is the addition of nucleotides at the junction (N region) of rearranged Ig heavy chain and T-cell receptor gene segments during the maturation of B- and T-cells. | + | [https://www.uniprot.org/uniprot/TDT_MOUSE TDT_MOUSE] Template-independent DNA polymerase which catalyzes the random addition of deoxynucleoside 5'-triphosphate to the 3'-end of a DNA initiator. One of the in vivo functions of this enzyme is the addition of nucleotides at the junction (N region) of rearranged Ig heavy chain and T-cell receptor gene segments during the maturation of B- and T-cells. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: DNA nucleotidylexotransferase]] | + | [[Category: Large Structures]] |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Mus musculus]] |
| - | [[Category: Delarue, M]] | + | [[Category: Delarue M]] |
| - | [[Category: Gouge, J]] | + | [[Category: Gouge J]] |
| - | [[Category: Terminal transferase]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Function
TDT_MOUSE Template-independent DNA polymerase which catalyzes the random addition of deoxynucleoside 5'-triphosphate to the 3'-end of a DNA initiator. One of the in vivo functions of this enzyme is the addition of nucleotides at the junction (N region) of rearranged Ig heavy chain and T-cell receptor gene segments during the maturation of B- and T-cells.
Publication Abstract from PubMed
Terminal deoxynucletidyl transferase (TdT) is overexpressed in some cancer types, where it might compete with pol mu driving the mutagenic repair of double strand breaks (DSBs) through the non homologous end joining (NHEJ) pathway. Here we report the discovery and characterization of pyrrolyl and indolyl diketo acids that specifically target TdT and behave as nucleotide-competitive inhibitors. These compounds show a selective toxicity towards MOLT-4 compared to HeLa cells that correlate well with in vitro selectivity for TdT. The binding site of two of these inhibitors was determined by co-crystallization with TdT, explaining why these compounds are competitive inhibitors of the deoxynucleotide triphosphate (dNTP). In addition, because of the observed dual localization of the phenyl substituent, these studies open the possibility to rationally design more potent compounds.
New Nucleotide-Competitive Non-Nucleoside Inhibitors of Terminal Deoxynucleotidyl Transferase: Discovery, Characterization and Crystal Structure in Complex with the Target.,Costi R, Cuzzucoli Crucitti G, Pescatori L, Messore A, Scipione L, Tortorella S, Amoroso A, Crespan E, Campiglia P, Maresca B, Novellino E, Gouge J, Delarue MH, Maga G, Di Santo R J Med Chem. 2013 Aug 22. PMID:23968551[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Costi R, Cuzzucoli Crucitti G, Pescatori L, Messore A, Scipione L, Tortorella S, Amoroso A, Crespan E, Campiglia P, Maresca B, Novellino E, Gouge J, Delarue MH, Maga G, Di Santo R. New Nucleotide-Competitive Non-Nucleoside Inhibitors of Terminal Deoxynucleotidyl Transferase: Discovery, Characterization and Crystal Structure in Complex with the Target. J Med Chem. 2013 Aug 22. PMID:23968551 doi:10.1021/jm4010187
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