2blc

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[[Image:2blc.gif|left|200px]]<br /><applet load="2blc" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:2blc.gif|left|200px]]
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caption="2blc, resolution 2.25&Aring;" />
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'''SP21 DOUBLE MUTANT P. VIVAX DIHYDROFOLATE REDUCTASE IN COMPLEX WITH DES-CHLOROPYRIMETHAMINE'''<br />
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{{Structure
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|PDB= 2blc |SIZE=350|CAPTION= <scene name='initialview01'>2blc</scene>, resolution 2.25&Aring;
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|SITE= <scene name='pdbsite=AC1:Mes+Binding+Site+For+Chain+A'>AC1</scene>
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|LIGAND= <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=CP7:6-ETHYL-5-PHENYLPYRIMIDINE-2,4-DIAMINE'>CP7</scene> and <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC ACID'>MES</scene>
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|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]
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|GENE=
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}}
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'''SP21 DOUBLE MUTANT P. VIVAX DIHYDROFOLATE REDUCTASE IN COMPLEX WITH DES-CHLOROPYRIMETHAMINE'''
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==Overview==
==Overview==
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==About this Structure==
==About this Structure==
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2BLC is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Plasmodium_vivax Plasmodium vivax] with <scene name='pdbligand=NDP:'>NDP</scene>, <scene name='pdbligand=CP7:'>CP7</scene> and <scene name='pdbligand=MES:'>MES</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Known structural/functional Site: <scene name='pdbsite=AC1:Mes+Binding+Site+For+Chain+A'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2BLC OCA].
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2BLC 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=2BLC OCA].
==Reference==
==Reference==
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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://ispc.weizmann.ac.il//pmbin/getpm?pmid=16135570 16135570]
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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: thymidylate synthase]]
[[Category: thymidylate synthase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:39:01 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 16:03:26 2008''

Revision as of 14:03, 20 March 2008

Image:2blc.gif


PDB ID 2blc

Drag the structure with the mouse to rotate
, resolution 2.25Å
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 DES-CHLOROPYRIMETHAMINE


Overview

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 Structure

2BLC is a Single protein structure of sequence from Plasmodium vivax. Full crystallographic information is available from OCA.

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:16135570

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