1cet
From Proteopedia
(New page: 200px<br /><applet load="1cet" size="450" color="white" frame="true" align="right" spinBox="true" caption="1cet, resolution 2.05Å" /> '''CHLOROQUINE BINDS IN...) |
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| - | [[Image:1cet.jpg|left|200px]]<br /><applet load="1cet" size=" | + | [[Image:1cet.jpg|left|200px]]<br /><applet load="1cet" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1cet, resolution 2.05Å" /> | caption="1cet, resolution 2.05Å" /> | ||
'''CHLOROQUINE BINDS IN THE COFACTOR BINDING SITE OF PLASMODIUM FALCIPARUM LACTATE DEHYDROGENASE.'''<br /> | '''CHLOROQUINE BINDS IN THE COFACTOR BINDING SITE OF PLASMODIUM FALCIPARUM LACTATE DEHYDROGENASE.'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Although the molecular mechanism by which chloroquine exerts its effects | + | Although the molecular mechanism by which chloroquine exerts its effects on the malarial parasite Plasmodium falciparum remains unclear, the drug has previously been found to interact specifically with the glycolytic enzyme lactate dehydrogenase from the parasite. In this study we have determined the crystal structure of the complex between chloroquine and P. falciparum lactate dehydrogenase. The bound chloroquine is clearly seen within the NADH binding pocket of the enzyme, occupying a position similar to that of the adenyl ring of the cofactor. Chloroquine hence competes with NADH for binding to the enzyme, acting as a competitive inhibitor for this critical glycolytic enzyme. Specific interactions between the drug and amino acids unique to the malarial form of the enzyme suggest this binding is selective. Inhibition studies confirm that chloroquine acts as a weak inhibitor of lactate dehydrogenase, with mild selectivity for the parasite enzyme. As chloroquine has been shown to accumulate to millimolar concentrations within the food vacuole in the gut of the parasite, even low levels of inhibition may contribute to the biological efficacy of the drug. The structure of this enzyme-inhibitor complex provides a template from which the quinoline moiety might be modified to develop more efficient inhibitors of the enzyme. |
==About this Structure== | ==About this Structure== | ||
| - | 1CET 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 CLQ as [http://en.wikipedia.org/wiki/ligand ligand]. 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:// | + | 1CET 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=CLQ:'>CLQ</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. 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=1CET OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Plasmodium falciparum]] | [[Category: Plasmodium falciparum]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Brady, R | + | [[Category: Brady, R L.]] |
| - | [[Category: Read, J | + | [[Category: Read, J A.]] |
| - | [[Category: Sessions, R | + | [[Category: Sessions, R B.]] |
[[Category: Tranter, R.]] | [[Category: Tranter, R.]] | ||
| - | [[Category: Wilkinson, K | + | [[Category: Wilkinson, K W.]] |
[[Category: CLQ]] | [[Category: CLQ]] | ||
[[Category: inhibitor]] | [[Category: inhibitor]] | ||
| Line 24: | Line 24: | ||
[[Category: tricarboxylic acid cycle]] | [[Category: tricarboxylic acid cycle]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:05:20 2008'' |
Revision as of 10:05, 21 February 2008
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CHLOROQUINE BINDS IN THE COFACTOR BINDING SITE OF PLASMODIUM FALCIPARUM LACTATE DEHYDROGENASE.
Overview
Although the molecular mechanism by which chloroquine exerts its effects on the malarial parasite Plasmodium falciparum remains unclear, the drug has previously been found to interact specifically with the glycolytic enzyme lactate dehydrogenase from the parasite. In this study we have determined the crystal structure of the complex between chloroquine and P. falciparum lactate dehydrogenase. The bound chloroquine is clearly seen within the NADH binding pocket of the enzyme, occupying a position similar to that of the adenyl ring of the cofactor. Chloroquine hence competes with NADH for binding to the enzyme, acting as a competitive inhibitor for this critical glycolytic enzyme. Specific interactions between the drug and amino acids unique to the malarial form of the enzyme suggest this binding is selective. Inhibition studies confirm that chloroquine acts as a weak inhibitor of lactate dehydrogenase, with mild selectivity for the parasite enzyme. As chloroquine has been shown to accumulate to millimolar concentrations within the food vacuole in the gut of the parasite, even low levels of inhibition may contribute to the biological efficacy of the drug. The structure of this enzyme-inhibitor complex provides a template from which the quinoline moiety might be modified to develop more efficient inhibitors of the enzyme.
About this Structure
1CET is a Single protein structure of sequence from Plasmodium falciparum with as ligand. Active as L-lactate dehydrogenase, with EC number 1.1.1.27 Full crystallographic information is available from OCA.
Reference
Chloroquine binds in the cofactor binding site of Plasmodium falciparum lactate dehydrogenase., Read JA, Wilkinson KW, Tranter R, Sessions RB, Brady RL, J Biol Chem. 1999 Apr 9;274(15):10213-8. PMID:10187806
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