|
|
| (2 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| | | | |
| | ==Plasmodium falciparum thymidylate kinase in complex with a urea-alpha- deoxythymidine inhibitor== | | ==Plasmodium falciparum thymidylate kinase in complex with a urea-alpha- deoxythymidine inhibitor== |
| - | <StructureSection load='2yoh' size='340' side='right' caption='[[2yoh]], [[Resolution|resolution]] 1.60Å' scene=''> | + | <StructureSection load='2yoh' size='340' side='right'caption='[[2yoh]], [[Resolution|resolution]] 1.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2yoh]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Plaf7 Plaf7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YOH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2YOH FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2yoh]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YOH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2YOH FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=WMJ:1-[[(2R,3S,5S)-5-[5-METHYL-2,4-BIS(OXIDANYLIDENE)PYRIMIDIN-1-YL]-3-OXIDANYL-OXOLAN-2-YL]METHYL]-3-(4-NITROPHENYL)UREA'>WMJ</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]] 1.6Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2wwf|2wwf]], [[2wwg|2wwg]], [[2wwh|2wwh]], [[2wwi|2wwi]], [[2yof|2yof]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=WMJ:1-[[(2R,3S,5S)-5-[5-METHYL-2,4-BIS(OXIDANYLIDENE)PYRIMIDIN-1-YL]-3-OXIDANYL-OXOLAN-2-YL]METHYL]-3-(4-NITROPHENYL)UREA'>WMJ</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=2yoh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2yoh OCA], [https://pdbe.org/2yoh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2yoh RCSB], [https://www.ebi.ac.uk/pdbsum/2yoh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2yoh ProSAT]</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=2yoh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2yoh OCA], [http://pdbe.org/2yoh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2yoh RCSB], [http://www.ebi.ac.uk/pdbsum/2yoh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2yoh ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/KTHY_PLAF7 KTHY_PLAF7] Catalyzes the phosphorylation of thymidine monophosphate (dTMP) to thymidine diphosphate (dTDP), the immediate precursor for the DNA building block dTTP (PubMed:18477629, PubMed:19126267, PubMed:31934749, PubMed:20353400). Can also phosphorylate dGMP and to a lesser extent GMP, dUMP and dIMP (PubMed:18477629, PubMed:19126267, PubMed:31934749, PubMed:20353400). Can use either ATP or dATP as phosphate donors in presence of Mg(2+) (PubMed:18477629).<ref>PMID:18477629</ref> <ref>PMID:19126267</ref> <ref>PMID:20353400</ref> <ref>PMID:31934749</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 20: |
Line 21: |
| | | | |
| | ==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: Plaf7]] | + | [[Category: Large Structures]] |
| - | [[Category: DTMP kinase]] | + | [[Category: Plasmodium falciparum 3D7]] |
| - | [[Category: Brannigan, J A]] | + | [[Category: Brannigan JA]] |
| - | [[Category: Carrero-Lerida, J]] | + | [[Category: Carrero-Lerida J]] |
| - | [[Category: Gilbert, I H]] | + | [[Category: Gilbert IH]] |
| - | [[Category: Gonzalez-Pacanowska, D]] | + | [[Category: Gonzalez-Pacanowska D]] |
| - | [[Category: Huaqing, C]] | + | [[Category: Huaqing C]] |
| - | [[Category: Read, K D]] | + | [[Category: Read KD]] |
| - | [[Category: Ruiz-Perez, L M]] | + | [[Category: Ruiz-Perez LM]] |
| - | [[Category: Silva, A P.G]] | + | [[Category: Silva APG]] |
| - | [[Category: Whittingham, J L]] | + | [[Category: Whittingham JL]] |
| - | [[Category: Wilson, K S]] | + | [[Category: Wilson KS]] |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Malaria]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
KTHY_PLAF7 Catalyzes the phosphorylation of thymidine monophosphate (dTMP) to thymidine diphosphate (dTDP), the immediate precursor for the DNA building block dTTP (PubMed:18477629, PubMed:19126267, PubMed:31934749, PubMed:20353400). Can also phosphorylate dGMP and to a lesser extent GMP, dUMP and dIMP (PubMed:18477629, PubMed:19126267, PubMed:31934749, PubMed:20353400). Can use either ATP or dATP as phosphate donors in presence of Mg(2+) (PubMed:18477629).[1] [2] [3] [4]
Publication Abstract from PubMed
Plasmodium falciparum thymidylate kinase (PfTMPK) is a key enzyme in pyrimidine nucleotide biosynthesis. 3-Trifluoromethyl-4-chloro-phenyl-urea-alpha-thymidine has been reported as an inhibitor of Mycobacterium tuberculosis TMPK (MtTMPK). Starting from this point, we designed, synthesized and evaluated a number of thymidine analogues as antimalarials. Both 5'-urea-alpha- and beta-thymidine derivatives were moderate inhibitors of PfTMPK and furthermore showed moderate inhibition of parasite growth. The structure of several enzyme-inhibitor complexes provides a basis for improved inhibitor design. However, we found that certain 5'-urea-alpha-thymidine analogues had antimalarial activity where inhibition of PfTMPK is not the major mode of action. Optimization of this series resulted in a compound with potent antimalarial activity (EC(50) = 28 nM; CC(50) = 29 muM).
Synthesis and evaluation of alpha-thymidine analogues as novel antimalarials.,Cui H, Carrero-Lerida J, Silva AP, Whittingham JL, Brannigan JA, Ruiz-Perez LM, Read KD, Wilson KS, Gonzalez-Pacanowska D, Gilbert IH J Med Chem. 2012 Dec 27;55(24):10948-57. doi: 10.1021/jm301328h. Epub 2012 Dec, 14. PMID:23240776[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kandeel M, Kitade Y. Molecular characterization, heterologous expression and kinetic analysis of recombinant Plasmodium falciparum thymidylate kinase. J Biochem. 2008 Aug;144(2):245-50. PMID:18477629 doi:10.1093/jb/mvn062
- ↑ Kandeel M, Ando T, Kitamura Y, Abdel-Aziz M, Kitade Y. Mutational, inhibitory and microcalorimetric analyses of Plasmodium falciparum TMP kinase. Implications for drug discovery. Parasitology. 2009 Jan;136(1):11-25. PMID:19126267 doi:10.1017/S0031182008005301
- ↑ Whittingham JL, Carrero-Lerida J, Brannigan JA, Ruiz-Perez LM, Silva AP, Fogg MJ, Wilkinson AJ, Gilbert IH, Wilson KS, Gonzalez-Pacanowska D. Structural basis for the efficient phosphorylation of AZT-MP (3'-azido-3'-deoxythymidine monophosphate) and dGMP by Plasmodium falciparum type I thymidylate kinase. Biochem J. 2010 May 27;428(3):499-509. PMID:20353400 doi:10.1042/BJ20091880
- ↑ Chen MD, Fucci IJ, Sinha K, Rule GS. dGMP Binding to Thymidylate Kinase from Plasmodium falciparum Shows Half-Site Binding and Induces Protein Dynamics at the Dimer Interface. Biochemistry. 2020 Feb 11;59(5):694-703. PMID:31934749 doi:10.1021/acs.biochem.9b00898
- ↑ Cui H, Carrero-Lerida J, Silva AP, Whittingham JL, Brannigan JA, Ruiz-Perez LM, Read KD, Wilson KS, Gonzalez-Pacanowska D, Gilbert IH. Synthesis and evaluation of alpha-thymidine analogues as novel antimalarials. J Med Chem. 2012 Dec 27;55(24):10948-57. doi: 10.1021/jm301328h. Epub 2012 Dec, 14. PMID:23240776 doi:10.1021/jm301328h
|
