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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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.71Å</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='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='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='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='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'>[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;">
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| - | == Publication Abstract from PubMed ==
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| - | 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.
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| - | 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<ref>PMID:23043329</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | <div class="pdbe-citations 4gsy" style="background-color:#fffaf0;"></div>
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| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Thymidylate kinase|Thymidylate kinase]] | + | *[[Thymidylate kinase 3D structures|Thymidylate kinase 3D structures]] |
| - | == References ==
| + | |
| - | <references/>
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| | __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]]
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| - | [[Category: Kinase activity]]
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| - | [[Category: Nucleotide binding]]
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| - | [[Category: Thymidylate kinase activity]]
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| - | [[Category: Transferase]]
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| - | [[Category: Transferase activity]]
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| - | [[Category: Transferase-transferase inhibitor complex]]
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