2y8c: Difference between revisions
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==Plasmodium falciparum dUTPase in complex with a trityl ligand== | |||
<StructureSection load='2y8c' size='340' side='right'caption='[[2y8c]], [[Resolution|resolution]] 2.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2y8c]] is a 3 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=2Y8C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2Y8C 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]] 2.1Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DUQ:(2S)-2-[(2,4-DIOXOPYRIMIDIN-1-YL)METHYL]-N-(2-HYDROXYETHYL)-4-TRITYLOXY-BUTANAMIDE'>DUQ</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=2y8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2y8c OCA], [https://pdbe.org/2y8c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2y8c RCSB], [https://www.ebi.ac.uk/pdbsum/2y8c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2y8c ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q8II92_PLAF7 Q8II92_PLAF7] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
We report a series of beta-branched acyclic tritylated deoxyuridine analogues as inhibitors of Plasmodium falciparum deoxyuridine-5'-triphosphate nucleotidohydrolase (PfdUTPase), an enzyme involved in nucleotide metabolism that acts as first line of defence against uracil incorporation into DNA. Compounds were assayed against both PfdUTPase and intact parasites showing a correlation between enzyme inhibition and cellular assays. beta-Branched acyclic uridine analogues described here showed equal or slightly better potency and selectivity compared with previously reported analogues. The best inhibitor gave a K(i) of 0.5 muM against PfdUTPase with selectivity greater than 200-fold compared to the corresponding human enzyme and sub-micromolar growth inhibition of P. falciparum (EC(50) 0.6 muM). A crystal structure of the complex of PfdUTPase with one of the inhibitors shows that this acyclic derivative binds to the active site in a similar manner to that previously reported for a tritylated cyclic deoxyuridine derivative. | |||
beta-Branched acyclic nucleoside analogues as inhibitors of Plasmodium falciparum dUTPase.,Baragana B, McCarthy O, Sanchez P, Bosch-Navarrete C, Kaiser M, Brun R, Whittingham JL, Roberts SM, Zhou XX, Wilson KS, Johansson NG, Gonzalez-Pacanowska D, Gilbert IH Bioorg Med Chem. 2011 Apr 1;19(7):2378-91. Epub 2011 Feb 17. PMID:21411327<ref>PMID:21411327</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2y8c" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[DUTPase 3D structures|DUTPase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Plasmodium falciparum 3D7]] | |||
[[Category: Baragana B]] | |||
[[Category: Bosch C]] | |||
[[Category: Brun R]] | |||
[[Category: Gilbert IH]] | |||
[[Category: Gonzalez-Pacanowska D]] | |||
[[Category: Johansson NG]] | |||
[[Category: Kaiser M]] | |||
[[Category: McCarthy O]] | |||
[[Category: Roberts S]] | |||
[[Category: Sanchez P]] | |||
[[Category: Whittingham JL]] | |||
[[Category: Wilson KS]] | |||
[[Category: Zhou X-X]] | |||
Latest revision as of 13:47, 20 December 2023
Plasmodium falciparum dUTPase in complex with a trityl ligandPlasmodium falciparum dUTPase in complex with a trityl ligand
Structural highlights
FunctionPublication Abstract from PubMedWe report a series of beta-branched acyclic tritylated deoxyuridine analogues as inhibitors of Plasmodium falciparum deoxyuridine-5'-triphosphate nucleotidohydrolase (PfdUTPase), an enzyme involved in nucleotide metabolism that acts as first line of defence against uracil incorporation into DNA. Compounds were assayed against both PfdUTPase and intact parasites showing a correlation between enzyme inhibition and cellular assays. beta-Branched acyclic uridine analogues described here showed equal or slightly better potency and selectivity compared with previously reported analogues. The best inhibitor gave a K(i) of 0.5 muM against PfdUTPase with selectivity greater than 200-fold compared to the corresponding human enzyme and sub-micromolar growth inhibition of P. falciparum (EC(50) 0.6 muM). A crystal structure of the complex of PfdUTPase with one of the inhibitors shows that this acyclic derivative binds to the active site in a similar manner to that previously reported for a tritylated cyclic deoxyuridine derivative. beta-Branched acyclic nucleoside analogues as inhibitors of Plasmodium falciparum dUTPase.,Baragana B, McCarthy O, Sanchez P, Bosch-Navarrete C, Kaiser M, Brun R, Whittingham JL, Roberts SM, Zhou XX, Wilson KS, Johansson NG, Gonzalez-Pacanowska D, Gilbert IH Bioorg Med Chem. 2011 Apr 1;19(7):2378-91. Epub 2011 Feb 17. PMID:21411327[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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