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==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:// | <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://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='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='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='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='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='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'>[http:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/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> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
| Line 20: | Line 20: | ||
==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: Large Structures]] | |||
[[Category: Plaf7]] | [[Category: Plaf7]] | ||
[[Category: DTMP kinase]] | [[Category: DTMP kinase]] | ||
Revision as of 16:00, 22 July 2020
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
Publication Abstract from PubMedPlasmodium 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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