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4gfd

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==Thymidylate kinase (TMK) from S. Aureus in complex with TK-666==
==Thymidylate kinase (TMK) from S. Aureus in complex with TK-666==
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<StructureSection load='4gfd' size='340' side='right' caption='[[4gfd]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
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<StructureSection load='4gfd' size='340' side='right'caption='[[4gfd]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4gfd]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Staphylococcus_aureus_subsp._aureus_n315 Staphylococcus aureus subsp. aureus n315]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GFD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GFD FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4gfd]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_subsp._aureus_N315 Staphylococcus aureus subsp. aureus N315]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GFD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GFD 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=0YB:2-(3-BROMOPHENOXY)-4-{(1R)-3,3-DIMETHYL-1-[(3S)-3-(5-METHYL-2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-1(2H)-YL)PIPERIDIN-1-YL]BUTYL}BENZOIC+ACID'>0YB</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]] 1.8&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4f4i|4f4i]], [[4dwj|4dwj]], [[4eaq|4eaq]], [[4hdc|4hdc]]</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=0YB:2-(3-BROMOPHENOXY)-4-{(1R)-3,3-DIMETHYL-1-[(3S)-3-(5-METHYL-2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-1(2H)-YL)PIPERIDIN-1-YL]BUTYL}BENZOIC+ACID'>0YB</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SA0440, tmk ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=158879 Staphylococcus aureus subsp. aureus N315])</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=4gfd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gfd OCA], [https://pdbe.org/4gfd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gfd RCSB], [https://www.ebi.ac.uk/pdbsum/4gfd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gfd 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=4gfd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gfd OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4gfd RCSB], [http://www.ebi.ac.uk/pdbsum/4gfd 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_STAAM KTHY_STAAM] Phosphorylation of dTMP to form dTDP in both de novo and salvage pathways of dTTP synthesis (By similarity).
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There is an urgent need for new antibacterials that pinpoint novel targets and thereby avoid existing resistance mechanisms. We have created novel synthetic antibacterials through structure-based drug design that specifically target bacterial thymidylate kinase (TMK), a nucleotide kinase essential in the DNA synthesis pathway. A high-resolution structure shows compound TK-666 binding partly in the thymidine monophosphate substrate site, but also forming new induced-fit interactions that give picomolar affinity. TK-666 has potent, broad-spectrum Gram-positive microbiological activity (including activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus), bactericidal action with rapid killing kinetics, excellent target selectivity over the human ortholog, and low resistance rates. We demonstrate in vivo efficacy against S. aureus in a murine infected-thigh model. This work presents the first validation of TMK as a compelling antibacterial target and provides a rationale for pursuing novel clinical candidates for treating Gram-positive infections through TMK.
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In Vivo Validation of Thymidylate Kinase (TMK) with a Rationally Designed, Selective Antibacterial Compound.,Keating TA, Newman JV, Olivier NB, Otterson LG, Andrews B, Boriack-Sjodin PA, Breen JN, Doig P, Dumas J, Gangl E, Green OM, Guler SY, Hentemann MF, Joseph-McCarthy D, Kawatkar S, Kutschke A, Loch JT, McKenzie AR, Pradeepan S, Prasad S, Martinez-Botella G ACS Chem Biol. 2012 Aug 28. PMID:22908966<ref>PMID:22908966</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 n315]]
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[[Category: Large Structures]]
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[[Category: DTMP kinase]]
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[[Category: Staphylococcus aureus subsp. aureus N315]]
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[[Category: Keating, T]]
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[[Category: Keating T]]
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[[Category: Martinez-Botella, G]]
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[[Category: Martinez-Botella G]]
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[[Category: Olivier, N B]]
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[[Category: Olivier NB]]
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[[Category: Kinase]]
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[[Category: Soluble]]
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[[Category: Thymidine monphosphate]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

Thymidylate kinase (TMK) from S. Aureus in complex with TK-666

PDB ID 4gfd

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