1t26: Difference between revisions

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Revision as of 15:12, 20 March 2008

File:1t26.gif

, resolution 1.80Å

Ligands:

and

Gene:

LDH (Plasmodium falciparum)

Activity:

L-lactate dehydrogenase, with EC number 1.1.1.27

Coordinates:

save as pdb, mmCIF, xml

Plasmodium falciparum lactate dehydrogenase complexed with NADH and 4-hydroxy-1,2,5-thiadiazole-3-carboxylic acid

OverviewOverview

Plasmodium falciparum, the causative agent of malaria, relies extensively on glycolysis coupled with homolactic fermentation during its blood-borne stages for energy production. Selective inhibitors of the parasite lactate dehydrogenase (LDH), central to NAD(+) regeneration, therefore potentially provide a route to new antimalarial drugs directed against a novel molecular target. A series of heterocyclic, azole-based compounds are described that preferentially inhibit P. falciparum LDH at sub-micromolar concentrations, typically at concentrations about 100-fold lower than required for human lactate dehydrogenase inhibition. Crystal structures show these competitive inhibitors form a network of interactions with amino acids within the active site of the enzyme, stacking alongside the nicotinamide ring of the NAD(+) cofactor. These compounds display modest activity against parasitized erythrocytes, including parasite strains with known resistance to existing anti-malarials and against Plasmodium berghei in BALB/c mice. Initial toxicity data suggest the azole derivatives have generally low cytotoxicity, and preliminary pharmoco-kinetic data show favorable bioavailability and circulation times. These encouraging results suggest that further enhancement of these structures may yield candidates suitable for consideration as new therapeutics for the treatment of malaria. In combination these studies also provide strong support for the validity of targeting the Plasmodium glycolytic pathway and, in particular, LDH in the search for novel anti-malarials.

About this StructureAbout this Structure

1T26 is a Single protein structure of sequence from Plasmodium falciparum. Full crystallographic information is available from OCA.

ReferenceReference

Identification and activity of a series of azole-based compounds with lactate dehydrogenase-directed anti-malarial activity., Cameron A, Read J, Tranter R, Winter VJ, Sessions RB, Brady RL, Vivas L, Easton A, Kendrick H, Croft SL, Barros D, Lavandera JL, Martin JJ, Risco F, Garcia-Ochoa S, Gamo FJ, Sanz L, Leon L, Ruiz JR, Gabarro R, Mallo A, Gomez de las Heras F, J Biol Chem. 2004 Jul 23;279(30):31429-39. Epub 2004 Apr 26. PMID:15117937

Page seeded by OCA on Thu Mar 20 14:12:43 2008

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OCA

@@ Line 1: / Line 1: @@
-[[Image:1t26.gif|left|200px]]<br /><applet load="1t26" size="350" color="white" frame="true" align="right" spinBox="true"
+[[Image:1t26.gif|left|200px]]
-caption="1t26, resolution 1.80&Aring;" />
-'''Plasmodium falciparum lactate dehydrogenase complexed with NADH and 4-hydroxy-1,2,5-thiadiazole-3-carboxylic acid'''<br />
+ {{Structure
+|PDB= 1t26 |SIZE=350|CAPTION= <scene name='initialview01'>1t26</scene>, resolution 1.80&Aring;
+|SITE=
+|LIGAND= <scene name='pdbligand=NAI:1,4-DIHYDRONICOTINAMIDE+ADENINE+DINUCLEOTIDE'>NAI</scene> and <scene name='pdbligand=GBD:4-HYDROXY-1,2,5-THIADIAZOLE-3-CARBOXYLIC ACID'>GBD</scene>
+|ACTIVITY= [http://en.wikipedia.org/wiki/L-lactate_dehydrogenase L-lactate dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.27 1.1.1.27]
+|GENE= LDH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5833 Plasmodium falciparum])
+}}
+'''Plasmodium falciparum lactate dehydrogenase complexed with NADH and 4-hydroxy-1,2,5-thiadiazole-3-carboxylic acid'''
 ==Overview==
@@ Line 7: / Line 16: @@
 ==About this Structure==
-T26 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum] with <scene name='pdbligand=NAI:'>NAI</scene> and <scene name='pdbligand=GBD:'>GBD</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/L-lactate_dehydrogenase L-lactate dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.27 1.1.1.27] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1T26 OCA].
+T26 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1T26 OCA].
 ==Reference==
-Identification and activity of a series of azole-based compounds with lactate dehydrogenase-directed anti-malarial activity., Cameron A, Read J, Tranter R, Winter VJ, Sessions RB, Brady RL, Vivas L, Easton A, Kendrick H, Croft SL, Barros D, Lavandera JL, Martin JJ, Risco F, Garcia-Ochoa S, Gamo FJ, Sanz L, Leon L, Ruiz JR, Gabarro R, Mallo A, Gomez de las Heras F, J Biol Chem. 2004 Jul 23;279(30):31429-39. Epub 2004 Apr 26. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15117937 15117937]
+Identification and activity of a series of azole-based compounds with lactate dehydrogenase-directed anti-malarial activity., Cameron A, Read J, Tranter R, Winter VJ, Sessions RB, Brady RL, Vivas L, Easton A, Kendrick H, Croft SL, Barros D, Lavandera JL, Martin JJ, Risco F, Garcia-Ochoa S, Gamo FJ, Sanz L, Leon L, Ruiz JR, Gabarro R, Mallo A, Gomez de las Heras F, J Biol Chem. 2004 Jul 23;279(30):31429-39. Epub 2004 Apr 26. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15117937 15117937]
 [[Category: L-lactate dehydrogenase]]
 [[Category: Plasmodium falciparum]]
@@ Line 40: / Line 49: @@
 [[Category: protein-ligand complex]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:09:06 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 14:12:43 2008''