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| - | ==NEW 5-BENZYLIDENETHIAZOLIDINE-4-ONE INHIBITORS OF BACTERIAL MURD LIGASE: DESIGN, SYNTHESIS, CRYSTAL STRUCTURES, AND BIOLOGICAL EVALUATION== | + | ==New 5-Benzylidenethiazolidine-4-one Inhibitors of Bacterial MurD Ligase: Design, Synthesis, Crystal Structures, and Biological Evaluation== |
| - | <StructureSection load='2y67' size='340' side='right' caption='[[2y67]], [[Resolution|resolution]] 1.85Å' scene=''> | + | <StructureSection load='2y67' size='340' side='right'caption='[[2y67]], [[Resolution|resolution]] 1.85Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2y67]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Ecoli Ecoli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Y67 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2Y67 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2y67]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Y67 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2Y67 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=N21:(2R)-2-[[4-[[4-[(Z)-(2,4-DIOXO-1,3-THIAZOLIDIN-5-YLIDENE)METHYL]PHENOXY]METHYL]PHENYL]SULFONYLAMINO]PENTANEDIOIC+ACID'>N21</scene>, <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]] 1.85Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=KCX:LYSINE+NZ-CARBOXYLIC+ACID'>KCX</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=KCX:LYSINE+NZ-CARBOXYLIC+ACID'>KCX</scene>, <scene name='pdbligand=N21:(2R)-2-[[4-[[4-[(Z)-(2,4-DIOXO-1,3-THIAZOLIDIN-5-YLIDENE)METHYL]PHENOXY]METHYL]PHENYL]SULFONYLAMINO]PENTANEDIOIC+ACID'>N21</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">[[2uuo|2uuo]], [[2jfg|2jfg]], [[4uag|4uag]], [[2uag|2uag]], [[3uag|3uag]], [[1e0d|1e0d]], [[2vte|2vte]], [[2jff|2jff]], [[1eeh|1eeh]], [[2x5o|2x5o]], [[2wjp|2wjp]], [[2vtd|2vtd]], [[2y1o|2y1o]], [[1uag|1uag]], [[2jfh|2jfh]], [[2uup|2uup]], [[2y66|2y66]], [[2y68|2y68]]</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=2y67 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2y67 OCA], [https://pdbe.org/2y67 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2y67 RCSB], [https://www.ebi.ac.uk/pdbsum/2y67 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2y67 ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/UDP-N-acetylmuramoyl-L-alanine--D-glutamate_ligase UDP-N-acetylmuramoyl-L-alanine--D-glutamate ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.2.9 6.3.2.9] </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=2y67 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2y67 OCA], [http://pdbe.org/2y67 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2y67 RCSB], [http://www.ebi.ac.uk/pdbsum/2y67 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2y67 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MURD_ECOLI MURD_ECOLI]] Cell wall formation. Catalyzes the addition of glutamate to the nucleotide precursor UDP-N-acetylmuramoyl-L-alanine (UMA).[HAMAP-Rule:MF_00639] | + | [https://www.uniprot.org/uniprot/MURD_ECOLI MURD_ECOLI] Cell wall formation. Catalyzes the addition of glutamate to the nucleotide precursor UDP-N-acetylmuramoyl-L-alanine (UMA).[HAMAP-Rule:MF_00639] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[MurD ligase|MurD ligase]] | + | *[[Mur ligase|Mur ligase]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Ecoli]] | + | [[Category: Escherichia coli K-12]] |
| - | [[Category: UDP-N-acetylmuramoyl-L-alanine--D-glutamate ligase]] | + | [[Category: Large Structures]] |
| - | [[Category: Blanot, D]] | + | [[Category: Blanot D]] |
| - | [[Category: Contreras-Martel, C]] | + | [[Category: Contreras-Martel C]] |
| - | [[Category: Dessen, A]] | + | [[Category: Dessen A]] |
| - | [[Category: Gobec, S]] | + | [[Category: Gobec S]] |
| - | [[Category: Kikelj, D]] | + | [[Category: Kikelj D]] |
| - | [[Category: Kovac, A]] | + | [[Category: Kovac A]] |
| - | [[Category: Muller-Premru, M]] | + | [[Category: Muller-Premru M]] |
| - | [[Category: Patin, D]] | + | [[Category: Patin D]] |
| - | [[Category: Peterlin-Masic, L]] | + | [[Category: Peterlin-Masic L]] |
| - | [[Category: Sink, R]] | + | [[Category: Sink R]] |
| - | [[Category: Tomasic, T]] | + | [[Category: Tomasic T]] |
| - | [[Category: Zega, A]] | + | [[Category: Zega A]] |
| - | [[Category: Zidar, N]] | + | [[Category: Zidar N]] |
| - | [[Category: Atp-binding]]
| + | |
| - | [[Category: Cell cycle]]
| + | |
| - | [[Category: Cell division]]
| + | |
| - | [[Category: Cell shape]]
| + | |
| - | [[Category: Cell wall]]
| + | |
| - | [[Category: Cell wall biogenesis/degradation]]
| + | |
| - | [[Category: Ligase]]
| + | |
| - | [[Category: Nucleotide-binding]]
| + | |
| - | [[Category: Peptidoglycan synthesis]]
| + | |
| - | [[Category: Uma]]
| + | |
| Structural highlights
Function
MURD_ECOLI Cell wall formation. Catalyzes the addition of glutamate to the nucleotide precursor UDP-N-acetylmuramoyl-L-alanine (UMA).[HAMAP-Rule:MF_00639]
Publication Abstract from PubMed
Mur ligases (MurC-MurF), a group of bacterial enzymes that catalyze four consecutive steps in the formation of cytoplasmic peptidoglycan precursor, are becoming increasingly adopted as targets in antibacterial drug design. Based on the crystal structure of MurD cocrystallized with thiazolidine-2,4-dione inhibitor I, we have designed, synthesized, and evaluated a series of improved glutamic acid containing 5-benzylidenerhodanine and 5-benzylidenethiazolidine-2,4-dione inhibitors of MurD with IC(50) values up to 28muM. Inhibitor 37, with an IC(50) of 34muM, displays a weak antibacterial activity against S. aureus ATCC 29213 and E. faecalis ATCC 29212 with minimal inhibitory concentrations of 128mug/mL. High-resolution crystal structures of MurD in complex with two new inhibitors (compounds 23 and 51) reveal details of their binding modes within the active site and provide valuable information for further structure-based optimization.
New 5-benzylidenethiazolidin-4-one inhibitors of bacterial MurD ligase: Design, synthesis, crystal structures, and biological evaluation.,Zidar N, Tomasic T, Sink R, Kovac A, Patin D, Blanot D, Contreras-Martel C, Dessen A, Premru MM, Zega A, Gobec S, Masic LP, Kikelj D Eur J Med Chem. 2011 Sep 17. PMID:21963114[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Zidar N, Tomasic T, Sink R, Kovac A, Patin D, Blanot D, Contreras-Martel C, Dessen A, Premru MM, Zega A, Gobec S, Masic LP, Kikelj D. New 5-benzylidenethiazolidin-4-one inhibitors of bacterial MurD ligase: Design, synthesis, crystal structures, and biological evaluation. Eur J Med Chem. 2011 Sep 17. PMID:21963114 doi:10.1016/j.ejmech.2011.09.017
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