2q8z: Difference between revisions
New page: left|200px<br /><applet load="2q8z" size="350" color="white" frame="true" align="right" spinBox="true" caption="2q8z, resolution 1.80Å" /> '''Crystal structure of... |
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==Overview== | ==Overview== | ||
Malaria, caused by Plasmodia parasites, has re-emerged as a major problem, imposing its fatal effects on human health, especially due to multidrug | Malaria, caused by Plasmodia parasites, has re-emerged as a major problem, imposing its fatal effects on human health, especially due to multidrug resistance. In Plasmodia, orotidine 5'-monophosphate decarboxylase (ODCase) is an essential enzyme for the de novo synthesis of uridine 5'-monophosphate. Impairing ODCase in these pathogens is a promising strategy to develop novel classes of therapeutics. Encouraged by our recent discovery that 6-iodo uridine is a potent inhibitor of P. falciparum, we investigated the structure-activity relationships of various C6 derivatives of UMP. 6-Cyano, 6-azido, 6-amino, 6-methyl, 6- N-methylamino, and 6- N, N-dimethylamino derivatives of uridine were evaluated against P. falciparum. The mononucleotides of 6-cyano, 6-azido, 6-amino, and 6-methyl uridine derivatives were studied as inhibitors of plasmodial ODCase. 6-Azidouridine 5'-monophosphate is a potent covalent inhibitor of P. falciparum ODCase. 6-Methyluridine exhibited weak antimalarial activity against P. falciparum 3D7 isolate. 6- N-Methylamino and 6- N, N-dimethylamino uridine derivatives exhibited moderate antimalarial activities. | ||
==About this Structure== | ==About this Structure== | ||
2Q8Z is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ | 2Q8Z is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Plasmodium_falciparum_dd2 Plasmodium falciparum dd2] with <scene name='pdbligand=SO4:'>SO4</scene>, <scene name='pdbligand=NUP:'>NUP</scene>, <scene name='pdbligand=7PE:'>7PE</scene> and <scene name='pdbligand=PEG:'>PEG</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Known structural/functional Sites: <scene name='pdbsite=AC1:So4+Binding+Site+For+Residue+A+501'>AC1</scene>, <scene name='pdbsite=AC2:So4+Binding+Site+For+Residue+B+501'>AC2</scene>, <scene name='pdbsite=AC3:Nup+Binding+Site+For+Residue+A+401'>AC3</scene>, <scene name='pdbsite=AC4:Nup+Binding+Site+For+Residue+B+401'>AC4</scene>, <scene name='pdbsite=AC5:7pe+Binding+Site+For+Residue+A+601'>AC5</scene>, <scene name='pdbsite=AC6:Peg+Binding+Site+For+Residue+A+701'>AC6</scene> and <scene name='pdbsite=AC7:Peg+Binding+Site+For+Residue+B+701'>AC7</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Q8Z OCA]. | ||
==Reference== | ==Reference== | ||
Structure-Activity Relationships of C6-Uridine Derivatives Targeting Plasmodia Orotidine Monophosphate Decarboxylase., Bello AM, Poduch E, Liu Y, Wei L, Crandall I, Wang X, Dyanand C, Kain KC, Pai EF, Kotra LP, J Med Chem. 2008 Jan 12 | Structure-Activity Relationships of C6-Uridine Derivatives Targeting Plasmodia Orotidine Monophosphate Decarboxylase., Bello AM, Poduch E, Liu Y, Wei L, Crandall I, Wang X, Dyanand C, Kain KC, Pai EF, Kotra LP, J Med Chem. 2008 Feb 14;51(3):439-448. Epub 2008 Jan 12. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18189347 18189347] | ||
[[Category: Plasmodium falciparum | [[Category: Plasmodium falciparum dd2]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Bello, A | [[Category: Bello, A M.]] | ||
[[Category: Hui, R.]] | [[Category: Hui, R.]] | ||
[[Category: Kotra, L | [[Category: Kotra, L P.]] | ||
[[Category: Lau, W.]] | [[Category: Lau, W.]] | ||
[[Category: Liu, Y.]] | [[Category: Liu, Y.]] | ||
[[Category: Pai, E | [[Category: Pai, E F.]] | ||
[[Category: 7PE]] | [[Category: 7PE]] | ||
[[Category: NUP]] | [[Category: NUP]] | ||
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[[Category: plasmodium falciparum]] | [[Category: plasmodium falciparum]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:37:13 2008'' | ||
Revision as of 16:37, 21 February 2008
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Crystal structure of Plasmodium falciparum orotidine 5'-phosphate decarboxylase complexed with 6-amino-UMP
Overview
Malaria, caused by Plasmodia parasites, has re-emerged as a major problem, imposing its fatal effects on human health, especially due to multidrug resistance. In Plasmodia, orotidine 5'-monophosphate decarboxylase (ODCase) is an essential enzyme for the de novo synthesis of uridine 5'-monophosphate. Impairing ODCase in these pathogens is a promising strategy to develop novel classes of therapeutics. Encouraged by our recent discovery that 6-iodo uridine is a potent inhibitor of P. falciparum, we investigated the structure-activity relationships of various C6 derivatives of UMP. 6-Cyano, 6-azido, 6-amino, 6-methyl, 6- N-methylamino, and 6- N, N-dimethylamino derivatives of uridine were evaluated against P. falciparum. The mononucleotides of 6-cyano, 6-azido, 6-amino, and 6-methyl uridine derivatives were studied as inhibitors of plasmodial ODCase. 6-Azidouridine 5'-monophosphate is a potent covalent inhibitor of P. falciparum ODCase. 6-Methyluridine exhibited weak antimalarial activity against P. falciparum 3D7 isolate. 6- N-Methylamino and 6- N, N-dimethylamino uridine derivatives exhibited moderate antimalarial activities.
About this Structure
2Q8Z is a Single protein structure of sequence from Plasmodium falciparum dd2 with SO4, NUP, 7PE and PEG as ligands. Known structural/functional Sites: AC1, AC2, AC3, AC4, AC5, AC6 and AC7. Full crystallographic information is available from OCA.
Reference
Structure-Activity Relationships of C6-Uridine Derivatives Targeting Plasmodia Orotidine Monophosphate Decarboxylase., Bello AM, Poduch E, Liu Y, Wei L, Crandall I, Wang X, Dyanand C, Kain KC, Pai EF, Kotra LP, J Med Chem. 2008 Feb 14;51(3):439-448. Epub 2008 Jan 12. PMID:18189347
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