1t2c: Difference between revisions
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New page: left|200px<br /><applet load="1t2c" size="450" color="white" frame="true" align="right" spinBox="true" caption="1t2c, resolution 2.01Å" /> '''Plasmodium falciparu... |
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== | ==Plasmodium falciparum lactate dehydrogenase complexed with NADH== | ||
Plasmodium falciparum, the causative agent of malaria, relies extensively | <StructureSection load='1t2c' size='340' side='right'caption='[[1t2c]], [[Resolution|resolution]] 2.01Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[1t2c]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1T2C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1T2C FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.01Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAI:1,4-DIHYDRONICOTINAMIDE+ADENINE+DINUCLEOTIDE'>NAI</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1t2c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1t2c OCA], [https://pdbe.org/1t2c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1t2c RCSB], [https://www.ebi.ac.uk/pdbsum/1t2c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1t2c ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/LDH_PLAFD LDH_PLAFD] | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/t2/1t2c_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1t2c ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
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<ref>PMID:15117937</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
[[Category: | <div class="pdbe-citations 1t2c" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Lactate dehydrogenase 3D structures|Lactate dehydrogenase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Plasmodium falciparum]] | [[Category: Plasmodium falciparum]] | ||
[[Category: | [[Category: Barros D]] | ||
[[Category: | [[Category: Brady RL]] | ||
[[Category: | [[Category: Cameron A]] | ||
[[Category: | [[Category: Croft SL]] | ||
[[Category: | [[Category: De Las Heras FG]] | ||
[[Category: Easton | [[Category: Easton A]] | ||
[[Category: Gabarro | [[Category: Gabarro R]] | ||
[[Category: Gamo | [[Category: Gamo FJ]] | ||
[[Category: Garcia-Ochoa | [[Category: Garcia-Ochoa S]] | ||
[[Category: Kendrick H]] | |||
[[Category: Kendrick | [[Category: Lavandera JL]] | ||
[[Category: Lavandera | [[Category: Leon L]] | ||
[[Category: Leon | [[Category: Mallo A]] | ||
[[Category: Mallo | [[Category: Martin JJ]] | ||
[[Category: Martin | [[Category: Read J]] | ||
[[Category: Read | [[Category: Risco F]] | ||
[[Category: Risco | [[Category: Ruiz JR]] | ||
[[Category: Ruiz | [[Category: Sanz L]] | ||
[[Category: Sanz | [[Category: Sessions RB]] | ||
[[Category: Sessions | [[Category: Tranter R]] | ||
[[Category: Tranter | [[Category: Vivas L]] | ||
[[Category: Vivas | [[Category: Winter VJ]] | ||
[[Category: Winter | |||
Latest revision as of 09:24, 23 August 2023
Plasmodium falciparum lactate dehydrogenase complexed with NADHPlasmodium falciparum lactate dehydrogenase complexed with NADH
Structural highlights
FunctionEvolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedPlasmodium 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. 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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