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| | <StructureSection load='3n5e' size='340' side='right'caption='[[3n5e]], [[Resolution|resolution]] 2.26Å' scene=''> | | <StructureSection load='3n5e' size='340' side='right'caption='[[3n5e]], [[Resolution|resolution]] 2.26Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3n5e]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3N5E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3N5E FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3n5e]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3N5E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3N5E FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.26Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SCH:S-METHYL-THIO-CYSTEINE'>SCH</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SCH:S-METHYL-THIO-CYSTEINE'>SCH</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3n5g|3n5g]]</div></td></tr>
| + | |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TYMS, TS, OK/SW-cl.29 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Thymidylate_synthase Thymidylate synthase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.45 2.1.1.45] </span></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=3n5e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3n5e OCA], [https://pdbe.org/3n5e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3n5e RCSB], [https://www.ebi.ac.uk/pdbsum/3n5e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3n5e ProSAT]</span></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=3n5e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3n5e OCA], [https://pdbe.org/3n5e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3n5e RCSB], [https://www.ebi.ac.uk/pdbsum/3n5e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3n5e ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/TYSY_HUMAN TYSY_HUMAN]] Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.<ref>PMID:21876188</ref>
| + | [https://www.uniprot.org/uniprot/TYSY_HUMAN TYSY_HUMAN] Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.<ref>PMID:21876188</ref> |
| | <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: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Thymidylate synthase]]
| + | [[Category: Cardinale D]] |
| - | [[Category: Cardinale, D]] | + | [[Category: Costi MP]] |
| - | [[Category: Costi, M P]] | + | [[Category: Ferrari S]] |
| - | [[Category: Ferrari, S]] | + | [[Category: Guaitoli G]] |
| - | [[Category: Guaitoli, G]] | + | [[Category: Luciani R]] |
| - | [[Category: Luciani, R]] | + | [[Category: Mangani S]] |
| - | [[Category: Mangani, S]] | + | [[Category: Myllykallio H]] |
| - | [[Category: Myllykallio, H]] | + | [[Category: Pozzi C]] |
| - | [[Category: Pozzi, C]] | + | [[Category: Tondi D]] |
| - | [[Category: Tondi, D]] | + | |
| - | [[Category: Interface inhibitor]]
| + | |
| - | [[Category: Peptide inhibitor]]
| + | |
| - | [[Category: Protein-peptide complex]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
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| Structural highlights
Function
TYSY_HUMAN Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.[1]
Publication Abstract from PubMed
Human thymidylate synthase is a homodimeric enzyme that plays a key role in DNA synthesis and is a target for several clinically important anticancer drugs that bind to its active site. We have designed peptides to specifically target its dimer interface. Here we show through X-ray diffraction, spectroscopic, kinetic, and calorimetric evidence that the peptides do indeed bind at the interface of the dimeric protein and stabilize its di-inactive form. The "LR" peptide binds at a previously unknown binding site and shows a previously undescribed mechanism for the allosteric inhibition of a homodimeric enzyme. It inhibits the intracellular enzyme in ovarian cancer cells and reduces cellular growth at low micromolar concentrations in both cisplatin-sensitive and -resistant cells without causing protein overexpression. This peptide demonstrates the potential of allosteric inhibition of hTS for overcoming platinum drug resistance in ovarian cancer.
Protein-protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase.,Cardinale D, Guaitoli G, Tondi D, Luciani R, Henrich S, Salo-Ahen OM, Ferrari S, Marverti G, Guerrieri D, Ligabue A, Frassineti C, Pozzi C, Mangani S, Fessas D, Guerrini R, Ponterini G, Wade RC, Costi MP Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):E542-9. doi:, 10.1073/pnas.1104829108. Epub 2011 Jul 27. PMID:21795601[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Anderson DD, Quintero CM, Stover PJ. Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria. Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15163-8. doi:, 10.1073/pnas.1103623108. Epub 2011 Aug 26. PMID:21876188 doi:10.1073/pnas.1103623108
- ↑ Cardinale D, Guaitoli G, Tondi D, Luciani R, Henrich S, Salo-Ahen OM, Ferrari S, Marverti G, Guerrieri D, Ligabue A, Frassineti C, Pozzi C, Mangani S, Fessas D, Guerrini R, Ponterini G, Wade RC, Costi MP. Protein-protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase. Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):E542-9. doi:, 10.1073/pnas.1104829108. Epub 2011 Jul 27. PMID:21795601 doi:10.1073/pnas.1104829108
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