|
|
| Line 1: |
Line 1: |
| | | | |
| | ==Thymidylate kinase (TMK) from S. Aureus in complex with TK-666== | | ==Thymidylate kinase (TMK) from S. Aureus in complex with TK-666== |
| - | <StructureSection load='4gfd' size='340' side='right' caption='[[4gfd]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='4gfd' size='340' side='right'caption='[[4gfd]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4gfd]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Staan Staan]. 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> | + | <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"><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='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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4f4i|4f4i]], [[4dwj|4dwj]], [[4eaq|4eaq]], [[4hdc|4hdc]]</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='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 STAAN])</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://pdbe.org/4gfd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4gfd RCSB], [http://www.ebi.ac.uk/pdbsum/4gfd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4gfd ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/KTHY_STAAN KTHY_STAAN]] Phosphorylation of dTMP to form dTDP in both de novo and salvage pathways of dTTP synthesis.[HAMAP-Rule:MF_00165] | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 23: |
Line 20: |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Thymidylate kinase|Thymidylate kinase]] | + | *[[Thymidylate kinase 3D structures|Thymidylate kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Staan]] | + | [[Category: Large Structures]] |
| - | [[Category: DTMP kinase]] | + | [[Category: Staphylococcus aureus subsp. aureus N315]] |
| - | [[Category: Keating, T]] | + | [[Category: Keating T]] |
| - | [[Category: Martinez-Botella, G]] | + | [[Category: Martinez-Botella G]] |
| - | [[Category: Olivier, N B]] | + | [[Category: Olivier NB]] |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Soluble]]
| + | |
| - | [[Category: Thymidine monphosphate]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Function
KTHY_STAAM Phosphorylation of dTMP to form dTDP in both de novo and salvage pathways of dTTP synthesis (By similarity).
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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. In Vivo Validation of Thymidylate Kinase (TMK) with a Rationally Designed, Selective Antibacterial Compound. ACS Chem Biol. 2012 Aug 28. PMID:22908966 doi:http://dx.doi.org/10.1021/cb300316n
|
