3n5e: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Crystal Structure of human thymidylate synthase bound to a peptide inhibitor== | ==Crystal Structure of human thymidylate synthase bound to a peptide inhibitor== | ||
<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 [http://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[3n5e]] 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=3N5E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3N5E FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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='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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3n5g|3n5g]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3n5g|3n5g]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TYMS, TS, OK/SW-cl.29 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TYMS, TS, OK/SW-cl.29 ([http://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'>[http://en.wikipedia.org/wiki/Thymidylate_synthase Thymidylate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.45 2.1.1.45] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Thymidylate_synthase Thymidylate synthase], with EC number [http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3n5e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3n5e OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3n5e RCSB], [http://www.ebi.ac.uk/pdbsum/3n5e 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=3n5e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3n5e OCA], [http://pdbe.org/3n5e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3n5e RCSB], [http://www.ebi.ac.uk/pdbsum/3n5e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3n5e ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
| Line 20: | Line 21: | ||
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 3n5e" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
| Line 27: | Line 29: | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Human]] | ||
[[Category: Thymidylate synthase]] | [[Category: Thymidylate synthase]] | ||
[[Category: Cardinale, D]] | [[Category: Cardinale, D]] | ||
Revision as of 19:21, 4 August 2016
Crystal Structure of human thymidylate synthase bound to a peptide inhibitorCrystal Structure of human thymidylate synthase bound to a peptide inhibitor
Structural highlights
Function[TYSY_HUMAN] Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.[1] Publication Abstract from PubMedHuman 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 AlsoReferences
|
| ||||||||||||||||||||||||