6yt1: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Mtb TMK crystal structure in complex with compound 26== | ==Mtb TMK crystal structure in complex with compound 26== | ||
<StructureSection load='6yt1' size='340' side='right'caption='[[6yt1]]' scene=''> | <StructureSection load='6yt1' size='340' side='right'caption='[[6yt1]], [[Resolution|resolution]] 1.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YT1 OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6yt1]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YT1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YT1 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=PK5:2-ethyl-~{N}-[[4-[4-[5-methyl-2,4-bis(oxidanylidene)pyrimidin-1-yl]piperidin-1-yl]phenyl]methyl]-1,2,3,5,6,7,8,8~{a}-octahydroimidazo[1,2-a]pyridine-3-carboxamide'>PK5</scene></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=6yt1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yt1 OCA], [https://pdbe.org/6yt1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yt1 RCSB], [https://www.ebi.ac.uk/pdbsum/6yt1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yt1 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/KTHY_MYCTU KTHY_MYCTU] Catalyzes the reversible phosphorylation of deoxythymidine monophosphate (dTMP) to deoxythymidine diphosphate (dTDP), using ATP as its preferred phosphoryl donor. Situated at the junction of both de novo and salvage pathways of deoxythymidine triphosphate (dTTP) synthesis, is essential for DNA synthesis and cellular growth. Has a broad specificity for nucleoside triphosphates, being highly active with ATP or dATP as phosphate donors, and less active with ITP, GTP, CTP and UTP.[HAMAP-Rule:MF_00165] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
As the last enzyme in nucleotide synthesis as precursors for DNA replication, thymidylate kinase of M. tuberculosis (MtbTMPK) attracts significant interest as a target in the discovery of new anti-tuberculosis agents. Earlier, we discovered potent MtbTMPK inhibitors, but these generally suffered from poor antimycobacterial activity, which we hypothesize is due to poor bacterial uptake. To address this, we herein describe our efforts to equip previously reported MtbTMPK inhibitors with targeting moieties to increase the whole cell activity of the hybrid analogues. Introduction of a simplified Fe-chelating siderophore motif gave rise to analogue 17 that combined favorable enzyme inhibitory activity with significant activity against M. tuberculosis (MIC of 12.5 muM). Conjugation of MtbTMPK inhibitors with an imidazo[1,2-a]pyridine or 3,5-dinitrobenzamide scaffold afforded analogues 26, 27 and 28, with moderate MtbTMPK enzyme inhibitory potency, but sub-micromolar activity against mycobacteria without significant cytotoxicity. These results indicate that conjugation with structural motifs known to favor mycobacterial uptake may be a valid approach for discovering new antimycobacterial agents. | |||
Endeavors towards transformation of M. tuberculosis thymidylate kinase (MtbTMPK) inhibitors into potential antimycobacterial agents.,Jian Y, Merceron R, De Munck S, Forbes HE, Hulpia F, Risseeuw MDP, Van Hecke K, Savvides SN, Munier-Lehmann H, Boshoff HIM, Van Calenbergh S Eur J Med Chem. 2020 Jul 24;206:112659. doi: 10.1016/j.ejmech.2020.112659. PMID:32823003<ref>PMID:32823003</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6yt1" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Thymidylate kinase 3D structures|Thymidylate kinase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Mycobacterium tuberculosis H37Rv]] | |||
[[Category: De Munck S]] | [[Category: De Munck S]] | ||
[[Category: Jian Y]] | [[Category: Jian Y]] | ||
Latest revision as of 16:34, 24 January 2024
Mtb TMK crystal structure in complex with compound 26Mtb TMK crystal structure in complex with compound 26
Structural highlights
FunctionKTHY_MYCTU Catalyzes the reversible phosphorylation of deoxythymidine monophosphate (dTMP) to deoxythymidine diphosphate (dTDP), using ATP as its preferred phosphoryl donor. Situated at the junction of both de novo and salvage pathways of deoxythymidine triphosphate (dTTP) synthesis, is essential for DNA synthesis and cellular growth. Has a broad specificity for nucleoside triphosphates, being highly active with ATP or dATP as phosphate donors, and less active with ITP, GTP, CTP and UTP.[HAMAP-Rule:MF_00165] Publication Abstract from PubMedAs the last enzyme in nucleotide synthesis as precursors for DNA replication, thymidylate kinase of M. tuberculosis (MtbTMPK) attracts significant interest as a target in the discovery of new anti-tuberculosis agents. Earlier, we discovered potent MtbTMPK inhibitors, but these generally suffered from poor antimycobacterial activity, which we hypothesize is due to poor bacterial uptake. To address this, we herein describe our efforts to equip previously reported MtbTMPK inhibitors with targeting moieties to increase the whole cell activity of the hybrid analogues. Introduction of a simplified Fe-chelating siderophore motif gave rise to analogue 17 that combined favorable enzyme inhibitory activity with significant activity against M. tuberculosis (MIC of 12.5 muM). Conjugation of MtbTMPK inhibitors with an imidazo[1,2-a]pyridine or 3,5-dinitrobenzamide scaffold afforded analogues 26, 27 and 28, with moderate MtbTMPK enzyme inhibitory potency, but sub-micromolar activity against mycobacteria without significant cytotoxicity. These results indicate that conjugation with structural motifs known to favor mycobacterial uptake may be a valid approach for discovering new antimycobacterial agents. Endeavors towards transformation of M. tuberculosis thymidylate kinase (MtbTMPK) inhibitors into potential antimycobacterial agents.,Jian Y, Merceron R, De Munck S, Forbes HE, Hulpia F, Risseeuw MDP, Van Hecke K, Savvides SN, Munier-Lehmann H, Boshoff HIM, Van Calenbergh S Eur J Med Chem. 2020 Jul 24;206:112659. doi: 10.1016/j.ejmech.2020.112659. PMID:32823003[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||