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| | ==Crystal structure of thymidylate kinase from Staphylococcus aureus bound to inhibitor.== | | ==Crystal structure of thymidylate kinase from Staphylococcus aureus bound to inhibitor.== |
| - | <StructureSection load='4gsy' size='340' side='right' caption='[[4gsy]], [[Resolution|resolution]] 1.71Å' scene=''> | + | <StructureSection load='4gsy' size='340' side='right'caption='[[4gsy]], [[Resolution|resolution]] 1.71Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4gsy]] 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=4GSY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GSY FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4gsy]] 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=4GSY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GSY FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0Y5:4-{[(3S)-3-(5-METHYL-2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-1(2H)-YL)PIPERIDIN-1-YL]METHYL}-2-[3-(TRIFLUOROMETHYL)PHENOXY]BENZOIC+ACID'>0Y5</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0Y5:4-{[(3S)-3-(5-METHYL-2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-1(2H)-YL)PIPERIDIN-1-YL]METHYL}-2-[3-(TRIFLUOROMETHYL)PHENOXY]BENZOIC+ACID'>0Y5</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4f4i|4f4i]], [[4hej|4hej]], [[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=4gsy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gsy OCA], [https://pdbe.org/4gsy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gsy RCSB], [https://www.ebi.ac.uk/pdbsum/4gsy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gsy ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SA0440, SAR0483, 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=4gsy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gsy OCA], [http://pdbe.org/4gsy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4gsy RCSB], [http://www.ebi.ac.uk/pdbsum/4gsy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4gsy 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_STAAR KTHY_STAAR] 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 == |
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| | ==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: Larsen, N A]] | + | [[Category: Larsen NA]] |
| - | [[Category: Olivier, N B]] | + | [[Category: Olivier NB]] |
| - | [[Category: Atp binding]]
| + | |
| - | [[Category: Kinase activity]]
| + | |
| - | [[Category: Nucleotide binding]]
| + | |
| - | [[Category: Thymidylate kinase activity]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Transferase activity]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Function
KTHY_STAAR Phosphorylation of dTMP to form dTDP in both de novo and salvage pathways of dTTP synthesis (By similarity).
Publication Abstract from PubMed
Thymidylate kinase (TMK) is an essential enzyme in bacterial DNA synthesis. The deoxythymidine monophosphate (dTMP) substrate binding pocket was targeted in a rational-design, structure-supported effort yielding a unique series of antibacterial agents showing a novel, induced-fit binding mode. Lead optimization, aided by x-ray crystallography, led to picomolar inhibitors of both Streptococcus pneumoniae and Staphylococcus aureus TMK. MICs <1 ug/mL were achieved against methicillin-resistant S. aureus (MRSA), S. pneumoniae, and vancomycin-resistant Enterococcus (VRE). Log D adjustments yielded single diastereomers 14 (TK-666) and 46, showing a broad antibacterial spectrum against Gram-positive bacteria and excellent selectivity against the human thymidylate kinase ortholog.
Discovery of Selective and Potent Inhibitors of Gram-positive Bacterial Thymidylate Kinase (TMK).,Martinez-Botella G, Breen JN, Duffy JE, Dumas J, Geng B, Gowers IK, Green OM, Guler S, Hentemann MF, Hernandez-Juan FA, Joseph-McCarthy D, Kawatkar SP, Larsen NA, Lazari O, Loch JT, Macritchie JA, McKenzie AR, Newman JV, Olivier NB, Otterson LG, Owens AP, Read J, Sheppard DW, Keating TA J Med Chem. 2012 Oct 8. PMID:23043329[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Martinez-Botella G, Breen JN, Duffy JE, Dumas J, Geng B, Gowers IK, Green OM, Guler S, Hentemann MF, Hernandez-Juan FA, Joseph-McCarthy D, Kawatkar SP, Larsen NA, Lazari O, Loch JT, Macritchie JA, McKenzie AR, Newman JV, Olivier NB, Otterson LG, Owens AP, Read J, Sheppard DW, Keating TA. Discovery of Selective and Potent Inhibitors of Gram-positive Bacterial Thymidylate Kinase (TMK). J Med Chem. 2012 Oct 8. PMID:23043329 doi:http://dx.doi.org/10.1021/jm3011806
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