3c06: Difference between revisions
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==Lactobacillus CASEI Thymidylate Synthase Ternary Complex With DUMP and the Phtalimidic Derivative 14C in Multiple Binding Modes-Mode 1== | ==Lactobacillus CASEI Thymidylate Synthase Ternary Complex With DUMP and the Phtalimidic Derivative 14C in Multiple Binding Modes-Mode 1== | ||
<StructureSection load='3c06' size='340' side='right' caption='[[3c06]], [[Resolution|resolution]] 2.60Å' scene=''> | <StructureSection load='3c06' size='340' side='right' caption='[[3c06]], [[Resolution|resolution]] 2.60Å' scene=''> | ||
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3bz0|3bz0]], [[3byx|3byx]], [[3bnz|3bnz]], [[1tls|1tls]], [[3c0a|3c0a]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3bz0|3bz0]], [[3byx|3byx]], [[3bnz|3bnz]], [[1tls|1tls]], [[3c0a|3c0a]]</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=3c06 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3c06 OCA], [http://pdbe.org/3c06 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3c06 RCSB], [http://www.ebi.ac.uk/pdbsum/3c06 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=3c06 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3c06 OCA], [http://pdbe.org/3c06 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3c06 RCSB], [http://www.ebi.ac.uk/pdbsum/3c06 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3c06 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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Check<jmol> | Check<jmol> | ||
<jmolCheckbox> | <jmolCheckbox> | ||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/c0/3c06_consurf.spt"</scriptWhenChecked> | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/c0/3c06_consurf.spt"</scriptWhenChecked> | ||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | ||
<text>to colour the structure by Evolutionary Conservation</text> | <text>to colour the structure by Evolutionary Conservation</text> | ||
Revision as of 16:50, 7 November 2018
Lactobacillus CASEI Thymidylate Synthase Ternary Complex With DUMP and the Phtalimidic Derivative 14C in Multiple Binding Modes-Mode 1Lactobacillus CASEI Thymidylate Synthase Ternary Complex With DUMP and the Phtalimidic Derivative 14C in Multiple Binding Modes-Mode 1
Structural highlights
Function[TYSY_LACCA] Provides the sole de novo source of dTMP for DNA biosynthesis. 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 PubMedTo identify specific bacterial thymidylate synthase (TS) inhibitors, we exploited phenolphthalein (PTH), which inhibits both bacterial and human enzymes. The X-ray crystal structure of Lactobacillus casei TS (LcTS) that binds PTH showed multiple binding modes of the inhibitor, which prevented a classical structure-based drug design approach. To overcome this issue, we synthesized two phthalimidic libraries that were tested against TS enzymes and then we performed X-ray crystallographic screening of the active compounds. Compounds 6A, 8A, and 12A showed 40-fold higher affinity for bacterial TS than human TS. The X-ray crystallographic screening characterized the binding mode of six inhibitors in complexes with LcTS. Of these, 20A, 23A, and 24A showed a common unique binding mode, whereas 8A showed a different, unique binding mode. A comparative analysis of the LcTS X-ray complexes that were obtained with the pathogenic TS enabled the selection of compounds 8A and 23A as specific compounds and starting points to be exploited for the specific inhibition of pathogen enzymes. Identification of the binding modes of N-phenylphthalimides inhibiting bacterial thymidylate synthase through X-ray crystallography screening.,Mangani S, Cancian L, Leone R, Pozzi C, Lazzari S, Luciani R, Ferrari S, Costi MP J Med Chem. 2011 Aug 11;54(15):5454-67. Epub 2011 Jul 12. PMID:21696158[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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