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< | ==Lactobacillus CASEI Thymidylate Synthase Ternary Complex with DUMP and the Phtalimidic Derivative C00 in Multiple Binding Modes== | ||
<StructureSection load='3byx' size='340' side='right'caption='[[3byx]], [[Resolution|resolution]] 2.40Å' scene=''> | |||
You may | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3byx]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Lacticaseibacillus_casei Lacticaseibacillus casei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BYX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3BYX FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C00:2-(4-HYDROXYBIPHENYL-3-YL)-4-METHYL-1H-ISOINDOLE-1,3(2H)-DIONE'>C00</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</scene></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=3byx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3byx OCA], [https://pdbe.org/3byx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3byx RCSB], [https://www.ebi.ac.uk/pdbsum/3byx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3byx ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/TYSY_LACCA TYSY_LACCA] Provides the sole de novo source of dTMP for DNA biosynthesis. | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/by/3byx_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3byx ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
To 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<ref>PMID:21696158</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3byx" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
*[[Thymidylate synthase 3D structures|Thymidylate synthase 3D structures]] | |||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: Cancian | __TOC__ | ||
[[Category: Costi | </StructureSection> | ||
[[Category: Ferrari | [[Category: Lacticaseibacillus casei]] | ||
[[Category: Leone | [[Category: Large Structures]] | ||
[[Category: Luciani | [[Category: Cancian L]] | ||
[[Category: Mangani | [[Category: Costi MP]] | ||
[[Category: Ferrari S]] | |||
[[Category: Leone R]] | |||
[[Category: Luciani R]] | |||
[[Category: Mangani S]] | |||
Latest revision as of 17:53, 1 November 2023
Lactobacillus CASEI Thymidylate Synthase Ternary Complex with DUMP and the Phtalimidic Derivative C00 in Multiple Binding ModesLactobacillus CASEI Thymidylate Synthase Ternary Complex with DUMP and the Phtalimidic Derivative C00 in Multiple Binding Modes
Structural highlights
FunctionTYSY_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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