4qgg

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==TMK in complex with compound 46, 2-(3-CHLOROPHENOXY)-3-FLUORO-4-{(1R)-3-METHYL-1-[(3S)-3-(5-METHYL-2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-1(2H)-YL)PIPERIDIN-1-YL]BUTYL}BENZOIC ACID==
==TMK in complex with compound 46, 2-(3-CHLOROPHENOXY)-3-FLUORO-4-{(1R)-3-METHYL-1-[(3S)-3-(5-METHYL-2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-1(2H)-YL)PIPERIDIN-1-YL]BUTYL}BENZOIC ACID==
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<StructureSection load='4qgg' size='340' side='right' caption='[[4qgg]], [[Resolution|resolution]] 1.62&Aring;' scene=''>
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<StructureSection load='4qgg' size='340' side='right'caption='[[4qgg]], [[Resolution|resolution]] 1.62&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4qgg]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QGG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QGG FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4qgg]] 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=4QGG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QGG 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=32C:2-(3-CHLOROPHENOXY)-3-FLUORO-4-{(1R)-3-METHYL-1-[(3S)-3-(5-METHYL-2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-1(2H)-YL)PIPERIDIN-1-YL]BUTYL}BENZOIC+ACID'>32C</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]] 1.62&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4qg7|4qg7]], [[4qga|4qga]], [[4qgh|4qgh]]</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=32C:2-(3-CHLOROPHENOXY)-3-FLUORO-4-{(1R)-3-METHYL-1-[(3S)-3-(5-METHYL-2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-1(2H)-YL)PIPERIDIN-1-YL]BUTYL}BENZOIC+ACID'>32C</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=4qgg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qgg OCA], [https://pdbe.org/4qgg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qgg RCSB], [https://www.ebi.ac.uk/pdbsum/4qgg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qgg ProSAT]</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=4qgg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qgg OCA], [http://pdbe.org/4qgg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qgg RCSB], [http://www.ebi.ac.uk/pdbsum/4qgg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4qgg ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://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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[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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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Thymidylate kinase (TMK), an essential enzyme in bacterial DNA biosynthesis, is an attractive therapeutic target for the development of novel antibacterial agents, and we continue to explore TMK inhibitors with improved potency, protein binding, and pharmacokinetic potential. A structure-guided design approach was employed to exploit a previously unexplored region in Staphylococcus aureus TMK via novel interactions. These efforts produced compound 39, with 3 nM IC50 against S. aureus TMK and 2 mug/mL MIC against methicillin-resistant S. aureus (MRSA). This compound exhibits a striking inverted chiral preference for binding relative to earlier compounds and also has improved physical properties and pharmacokinetics over previously published compounds. An example of this new series was efficacious in a murine S. aureus infection model, suggesting that compounds like 39 are options for further work toward a new Gram-positive antibiotic by maintaining a balance of microbiological potency, low clearance, and low protein binding that can result in lower efficacious doses.
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Antibacterial Inhibitors of Gram-Positive Thymidylate Kinase: Structure-Activity Relationships and Chiral Preference of a New Hydrophobic Binding Region.,Kawatkar SP, Keating TA, Olivier NB, Breen JN, Green OM, Guler SY, Hentemann MF, Loch JT, McKenzie AR, Newman JV, Otterson LG, Martinez-Botella G J Med Chem. 2014 Jun 3. PMID:24828090<ref>PMID:24828090</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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<div class="pdbe-citations 4qgg" style="background-color:#fffaf0;"></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: DTMP kinase]]
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[[Category: Large Structures]]
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[[Category: Olivier, N B]]
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[[Category: Staphylococcus aureus subsp. aureus MRSA252]]
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[[Category: Soluble]]
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[[Category: Olivier NB]]
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[[Category: Thymidine monphosphate]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

TMK in complex with compound 46, 2-(3-CHLOROPHENOXY)-3-FLUORO-4-{(1R)-3-METHYL-1-[(3S)-3-(5-METHYL-2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-1(2H)-YL)PIPERIDIN-1-YL]BUTYL}BENZOIC ACID

PDB ID 4qgg

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