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4hej

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Discovery of Selective and Potent Inhibitors of Gram-positive Bacterial Thymidylate Kinase (TMK): Compund 16

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 ==Discovery of Selective and Potent Inhibitors of Gram-positive Bacterial Thymidylate Kinase (TMK): Compund 16==
-<StructureSection load='4hej' size='340' side='right' caption='[[4hej]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+<StructureSection load='4hej' size='340' side='right'caption='[[4hej]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4hej]] 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=4HEJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HEJ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4hej]] 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=4HEJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HEJ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=14D:5-METHYL-1-[(3S)-1-{3-[3-(TRIFLUOROMETHYL)PHENOXY]BENZYL}PIPERIDIN-3-YL]PYRIMIDINE-2,4(1H,3H)-DIONE'>14D</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]] 2&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gsy|4gsy]], [[4hdc|4hdc]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=14D:5-METHYL-1-[(3S)-1-{3-[3-(TRIFLUOROMETHYL)PHENOXY]BENZYL}PIPERIDIN-3-YL]PYRIMIDINE-2,4(1H,3H)-DIONE'>14D</scene></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 Staphylococcus aureus subsp. aureus N315])</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=4hej FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hej OCA], [https://pdbe.org/4hej PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hej RCSB], [https://www.ebi.ac.uk/pdbsum/4hej PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hej 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>
-<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=4hej FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hej OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4hej RCSB], [http://www.ebi.ac.uk/pdbsum/4hej PDBsum]</span></td></tr>
 </table>
-<div style="background-color:#fffaf0;">
+== Function ==
-== Publication Abstract from PubMed ==
+[https://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]
-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 &lt;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<ref>PMID:23043329</ref>
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
 ==See Also==
-*[[Thymidylate kinase|Thymidylate kinase]]
+*[[Thymidylate kinase 3D structures|Thymidylate kinase 3D structures]]
-== References ==
-<references/>
 __TOC__
 </StructureSection>
-[[Category: Staphylococcus aureus subsp. aureus n315]]
+[[Category: Large Structures]]
-[[Category: DTMP kinase]]
+[[Category: Staphylococcus aureus subsp. aureus N315]]
-[[Category: Breen, J]]
+[[Category: Breen J]]
-[[Category: Duffy, J]]
+[[Category: Duffy J]]
-[[Category: Dumas, J]]
+[[Category: Dumas J]]
-[[Category: Geng, B]]
+[[Category: Geng B]]
-[[Category: Gowers, I]]
+[[Category: Gowers I]]
-[[Category: Green, O]]
+[[Category: Green O]]
-[[Category: Guler, S]]
+[[Category: Guler S]]
-[[Category: Hentemann, M]]
+[[Category: Hentemann M]]
-[[Category: Hernandez-Juan, F]]
+[[Category: Hernandez-Juan F]]
-[[Category: Joseph-McCarthy, D]]
+[[Category: Joseph-McCarthy D]]
-[[Category: Kawatkar, S]]
+[[Category: Kawatkar S]]
-[[Category: Larsen, N]]
+[[Category: Larsen N]]
-[[Category: Lazari, O]]
+[[Category: Lazari O]]
-[[Category: Loch, J]]
+[[Category: Loch J]]
-[[Category: Macritchie, J]]
+[[Category: Macritchie J]]
-[[Category: Martinez-Botella, G]]
+[[Category: Martinez-Botella G]]
-[[Category: Antibacterial]]
-[[Category: Dna repair]]
-[[Category: Dtmp atp]]
-[[Category: Inhibitor]]
-[[Category: Kinase]]
-[[Category: Phosphorylation]]
-[[Category: Tmk]]
-[[Category: Tmp]]
-[[Category: Transferase-transferase inhibitor complex]]

4hej

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Discovery of Selective and Potent Inhibitors of Gram-positive Bacterial Thymidylate Kinase (TMK): Compund 16

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