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4hld

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==Sulfonylpiperidines as Novel, Antibacterial Inhibitors of Gram-Positive Thymidylate Kinase (TMK): Compound 11==
==Sulfonylpiperidines as Novel, Antibacterial Inhibitors of Gram-Positive Thymidylate Kinase (TMK): Compound 11==
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<StructureSection load='4hld' size='340' side='right' caption='[[4hld]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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<StructureSection load='4hld' size='340' side='right'caption='[[4hld]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4hld]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Staphylococcus_aureus_subsp._aureus_mrsa252 Staphylococcus aureus subsp. aureus mrsa252]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HLD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HLD FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4hld]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_subsp._aureus_MRSA252 Staphylococcus aureus subsp. aureus MRSA252]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HLD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HLD FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=16T:1-[(3S)-1-{[3-(3-CHLOROPHENOXY)-4-HYDROXYPHENYL]SULFONYL}PIPERIDIN-3-YL]-5-METHYLPYRIMIDINE-2,4(1H,3H)-DIONE'>16T</scene></td></tr>
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</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&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gfd|4gfd]], [[4hdc|4hdc]], [[4gsy|4gsy]], [[4hej|4hej]], [[4hlc|4hlc]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=16T:1-[(3S)-1-{[3-(3-CHLOROPHENOXY)-4-HYDROXYPHENYL]SULFONYL}PIPERIDIN-3-YL]-5-METHYLPYRIMIDINE-2,4(1H,3H)-DIONE'>16T</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SAR0483, tmk ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=282458 Staphylococcus aureus subsp. aureus MRSA252])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4hld FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hld OCA], [https://pdbe.org/4hld PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hld RCSB], [https://www.ebi.ac.uk/pdbsum/4hld PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hld ProSAT]</span></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/dTMP_kinase dTMP kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.4.9 2.7.4.9] </span></td></tr>
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<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=4hld FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hld OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4hld RCSB], [http://www.ebi.ac.uk/pdbsum/4hld PDBsum]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/KTHY_STAAR KTHY_STAAR] Phosphorylation of dTMP to form dTDP in both de novo and salvage pathways of dTTP synthesis (By similarity).
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Thymidylate kinase (TMK) is an essential enzyme for DNA synthesis in bacteria, phosphorylating deoxythymidine monophosphate (dTMP) to deoxythymidine diphosphate (dTDP), and thus is a potential new antibacterial drug target. Previously, we have described the first potent and selective inhibitors of Gram-positive TMK, leading to in vivo validation of the target. Here, a structure-guided design approach based on the initial series led to the discovery of novel sulfonylpiperidine inhibitors of TMK. Formation of hydrogen bonds with Arg48 in Staphylococcus aureus TMK was key to obtaining excellent enzyme affinity, as verified by protein crystallography. Replacement of a methylene linker in the series by a sulfonamide was accomplished with retention of binding conformation. Further optimization of logD yielded phenol derivative 11, a potent inhibitor of TMK showing excellent MICs against a broad spectrum of Gram-positive bacteria and &gt;10(5) selectivity versus the human TMK homologue.
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Sulfonylpiperidines as novel, antibacterial inhibitors of Gram-positive thymidylate kinase (TMK).,Martinez-Botella G, Loch JT, Green OM, Kawatkar SP, Olivier NB, Boriack-Sjodin PA, Keating TA Bioorg Med Chem Lett. 2013 Jan 1;23(1):169-73. doi: 10.1016/j.bmcl.2012.10.128., Epub 2012 Nov 5. PMID:23206863<ref>PMID:23206863</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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==See Also==
==See Also==
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*[[Thymidylate kinase|Thymidylate kinase]]
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*[[Thymidylate kinase 3D structures|Thymidylate kinase 3D structures]]
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Staphylococcus aureus subsp. aureus mrsa252]]
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[[Category: Large Structures]]
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[[Category: DTMP kinase]]
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[[Category: Staphylococcus aureus subsp. aureus MRSA252]]
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[[Category: Olivier, N]]
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[[Category: Olivier N]]
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[[Category: Kinase]]
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[[Category: Mrsa]]
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[[Category: Pipiridine]]
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[[Category: Thymidylate kinase]]
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[[Category: Tmk]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

Sulfonylpiperidines as Novel, Antibacterial Inhibitors of Gram-Positive Thymidylate Kinase (TMK): Compound 11

PDB ID 4hld

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