2bla: Difference between revisions

Revision as of 20:26, 3 May 2008

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 Page seeded by OCA on Sat May 3 20:26:57 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
 [[Image:2bla.gif|left|200px]]
- {{Structure
+<!--
-|PDB= 2bla |SIZE=350|CAPTION= <scene name='initialview01'>2bla</scene>, resolution 2.50&Aring;
+The line below this paragraph, containing "STRUCTURE_2bla", creates the "Structure Box" on the page.
-|SITE= <scene name='pdbsite=AC1:Mes+Binding+Site+For+Chain+A'>AC1</scene>
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=CP6:5-(4-CHLORO-PHENYL)-6-ETHYL-PYRIMIDINE-2,4-DIAMINE'>CP6</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>
+or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-|ACTIVITY= <span class='plainlinks'>[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] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE=
+-->
-|DOMAIN=
+{{STRUCTURE_2bla|  PDB=2bla  |  SCENE=  }}
-|RELATEDENTRY=
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2bla FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2bla OCA], [http://www.ebi.ac.uk/pdbsum/2bla PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2bla RCSB]</span>
-}}
 '''SP21 DOUBLE MUTANT P. VIVAX DIHYDROFOLATE REDUCTASE IN COMPLEX WITH PYRIMETHAMINE'''
@@ Line 33: / Line 30: @@
 [[Category: Walkinshaw, M D.]]
 [[Category: Yuthavong, Y.]]
-[[Category: dihydrofolate reductase]]
+[[Category: Dihydrofolate reductase]]
-[[Category: drug resistance]]
+[[Category: Drug resistance]]
-[[Category: malaria]]
+[[Category: Malaria]]
-[[Category: oxidoreductase]]
+[[Category: Oxidoreductase]]
-[[Category: plasmodium vivax]]
+[[Category: Plasmodium vivax]]
-[[Category: pyrimethamine]]
+[[Category: Pyrimethamine]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May  3 20:26:57 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 02:08:09 2008''