2bla: Difference between revisions
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[[Image:2bla.gif|left|200px]] | [[Image:2bla.gif|left|200px]] | ||
'''SP21 DOUBLE MUTANT P. VIVAX DIHYDROFOLATE REDUCTASE IN COMPLEX WITH PYRIMETHAMINE''' | {{Structure | ||
|PDB= 2bla |SIZE=350|CAPTION= <scene name='initialview01'>2bla</scene>, resolution 2.50Å | |||
|SITE= <scene name='pdbsite=AC1:Mes+Binding+Site+For+Chain+A'>AC1</scene> | |||
|LIGAND= <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=CP6:5-(4-CHLORO-PHENYL)-6-ETHYL-PYRIMIDINE-2,4-DIAMINE'>CP6</scene> and <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC ACID'>MES</scene> | |||
|ACTIVITY= [http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] | |||
|GENE= | |||
}} | |||
'''SP21 DOUBLE MUTANT P. VIVAX DIHYDROFOLATE REDUCTASE IN COMPLEX WITH PYRIMETHAMINE''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
2BLA is a [ | 2BLA is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Plasmodium_vivax Plasmodium vivax]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2BLA OCA]. | ||
==Reference== | ==Reference== | ||
Crystal structure of dihydrofolate reductase from Plasmodium vivax: pyrimethamine displacement linked with mutation-induced resistance., Kongsaeree P, Khongsuk P, Leartsakulpanich U, Chitnumsub P, Tarnchompoo B, Walkinshaw MD, Yuthavong Y, Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13046-51. Epub 2005 Aug 31. PMID:[http:// | Crystal structure of dihydrofolate reductase from Plasmodium vivax: pyrimethamine displacement linked with mutation-induced resistance., Kongsaeree P, Khongsuk P, Leartsakulpanich U, Chitnumsub P, Tarnchompoo B, Walkinshaw MD, Yuthavong Y, Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13046-51. Epub 2005 Aug 31. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16135570 16135570] | ||
[[Category: Dihydrofolate reductase]] | [[Category: Dihydrofolate reductase]] | ||
[[Category: Plasmodium vivax]] | [[Category: Plasmodium vivax]] | ||
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[[Category: pyrimethamine]] | [[Category: pyrimethamine]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 16:03:24 2008'' | ||
Revision as of 17:03, 20 March 2008
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| , resolution 2.50Å | |||||||
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| Sites: | |||||||
| Ligands: | , and | ||||||
| Activity: | Dihydrofolate reductase, with EC number 1.5.1.3 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
SP21 DOUBLE MUTANT P. VIVAX DIHYDROFOLATE REDUCTASE IN COMPLEX WITH PYRIMETHAMINE
OverviewOverview
Pyrimethamine (Pyr) targets dihydrofolate reductase of Plasmodium vivax (PvDHFR) as well as other malarial parasites, but its use as antimalarial is hampered by the widespread high resistance. Comparison of the crystal structures of PvDHFR from wild-type and the Pyr-resistant (SP21, Ser-58 --> Arg + Ser-117 --> Asn) strain as complexes with NADPH and Pyr or its analog lacking p-Cl (Pyr20) clearly shows that the steric conflict arising from the side chain of Asn-117 in the mutant enzyme, accompanied by the loss of binding to Ser-120, is mainly responsible for the reduction in binding of Pyr. Pyr20 still effectively inhibits both the wild-type and SP21 proteins, and the x-ray structures of these complexes show how Pyr20 fits into both active sites without steric strain. These structural insights suggest a general approach for developing new generations of antimalarial DHFR inhibitors that, by only occupying substrate space of the active site, would retain binding affinity with the mutant enzymes.
About this StructureAbout this Structure
2BLA is a Single protein structure of sequence from Plasmodium vivax. Full crystallographic information is available from OCA.
ReferenceReference
Crystal structure of dihydrofolate reductase from Plasmodium vivax: pyrimethamine displacement linked with mutation-induced resistance., Kongsaeree P, Khongsuk P, Leartsakulpanich U, Chitnumsub P, Tarnchompoo B, Walkinshaw MD, Yuthavong Y, Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13046-51. Epub 2005 Aug 31. PMID:16135570
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