5nq5: Difference between revisions
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==Mtb TMK crystal structure in complex with compound 1== | ==Mtb TMK crystal structure in complex with compound 1== | ||
<StructureSection load='5nq5' size='340' side='right' caption='[[5nq5]], [[Resolution|resolution]] 2.85Å' scene=''> | <StructureSection load='5nq5' size='340' side='right'caption='[[5nq5]], [[Resolution|resolution]] 2.85Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5nq5]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[5nq5]] is a 1 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=5NQ5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5NQ5 FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.85Å</td></tr> | ||
<tr id=' | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=952:5-methyl-1-[(3~{S})-1-[(3-phenoxyphenyl)methyl]piperidin-3-yl]pyrimidine-2,4-dione'>952</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=5nq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nq5 OCA], [https://pdbe.org/5nq5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5nq5 RCSB], [https://www.ebi.ac.uk/pdbsum/5nq5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5nq5 ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == 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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Mycobacterium tuberculosis H37Rv]] | ||
[[Category: Merceron R]] | |||
[[Category: Merceron | [[Category: Munier-Lehmann H]] | ||
[[Category: Munier-Lehmann | [[Category: Savvides S]] | ||
[[Category: Savvides | [[Category: Song L]] | ||
[[Category: Song | [[Category: Van Calenbergh S]] | ||
[[Category: | |||
Revision as of 16:21, 15 November 2023
Mtb TMK crystal structure in complex with compound 1Mtb TMK crystal structure in complex with compound 1
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 PubMedIn recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK ( MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure-activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance. Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors.,Song L, Merceron R, Gracia B, Quintana AL, Risseeuw MDP, Hulpia F, Cos P, Ainsa JA, Munier-Lehmann H, Savvides SN, Van Calenbergh S J Med Chem. 2018 Mar 15. doi: 10.1021/acs.jmedchem.7b01570. PMID:29510037[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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