2yoh: Difference between revisions

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New page: '''Unreleased structure''' The entry 2yoh is ON HOLD Authors: Huaqing, C., Carrero-Lerida, J., Silva, A.P.G., Whittingham, J.L., Brannigan, J.A., Ruiz-Perez, L.M., Read, K.D., Wilson, K...
 
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'''Unreleased structure'''


The entry 2yoh is ON HOLD
==Plasmodium falciparum thymidylate kinase in complex with a urea-alpha- deoxythymidine inhibitor==
<StructureSection load='2yoh' size='340' side='right'caption='[[2yoh]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
<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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6&#8491;</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='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>
</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;">
== 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).


Authors: Huaqing, C., Carrero-Lerida, J., Silva, A.P.G., Whittingham, J.L., Brannigan, J.A., Ruiz-Perez, L.M., Read, K.D., Wilson, K.S., Gonzalez-Pacanowska, D., Gilbert, I.H.
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<ref>PMID:23240776</ref>


Description: Plasmodium falciparum thymidylate kinase in complex with a urea-alpha-deoxythymidine inhibitor
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2yoh" style="background-color:#fffaf0;"></div>
 
==See Also==
*[[Thymidylate kinase 3D structures|Thymidylate kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Plasmodium falciparum 3D7]]
[[Category: Brannigan JA]]
[[Category: Carrero-Lerida J]]
[[Category: Gilbert IH]]
[[Category: Gonzalez-Pacanowska D]]
[[Category: Huaqing C]]
[[Category: Read KD]]
[[Category: Ruiz-Perez LM]]
[[Category: Silva APG]]
[[Category: Whittingham JL]]
[[Category: Wilson KS]]

Latest revision as of 13:57, 20 December 2023

Plasmodium falciparum thymidylate kinase in complex with a urea-alpha- deoxythymidine inhibitorPlasmodium falciparum thymidylate kinase in complex with a urea-alpha- deoxythymidine inhibitor

Structural highlights

2yoh is a 2 chain structure with sequence from Plasmodium falciparum 3D7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.6Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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

2yoh, resolution 1.60Å

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