4gfd
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<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> | <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> | ||
| - | </td></tr><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> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</td></tr> |
| + | <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> | ||
<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> | <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> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[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). | [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). | ||
| - | <div style="background-color:#fffaf0;"> | ||
| - | == Publication Abstract from PubMed == | ||
| - | 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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 4gfd" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
*[[Thymidylate kinase 3D structures|Thymidylate kinase 3D structures]] | *[[Thymidylate kinase 3D structures|Thymidylate kinase 3D structures]] | ||
| - | == References == | ||
| - | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Current revision
Thymidylate kinase (TMK) from S. Aureus in complex with TK-666
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