4gfd

<StructureSection load='4gfd' size='340' side='right' caption='[[4gfd]], [[Resolution|resolution]] 1.80&Aring;' scene=''>

<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>

</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>

<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>

<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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== 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.

 

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>

 

*[[Thymidylate kinase|Thymidylate kinase]]

[[Category: Staphylococcus aureus subsp. aureus n315]]

[[Category: DTMP kinase]]

[[Category: Keating, T]]

[[Category: Martinez-Botella, G]]

[[Category: Olivier, N B]]

[[Category: Transferase-transferase inhibitor complex]]