1xiv: Difference between revisions

Revision as of 02:16, 29 July 2008

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Template:STRUCTURE 1xiv

Plasmodium falciparum lactate dehydrogenase complexed with 2-({4-chloro-[hydroxy(methoxy)methyl]cyclohexyl}amino)ethane-1,1,2-triolPlasmodium falciparum lactate dehydrogenase complexed with 2-({4-chloro-[hydroxy(methoxy)methyl]cyclohexyl}amino)ethane-1,1,2-triol

Template:ABSTRACT PUBMED 15978953

About this StructureAbout this Structure

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

ReferenceReference

Mapping the binding site for gossypol-like inhibitors of Plasmodium falciparum lactate dehydrogenase., Conners R, Schambach F, Read J, Cameron A, Sessions RB, Vivas L, Easton A, Croft SL, Brady RL, Mol Biochem Parasitol. 2005 Aug;142(2):137-48. Epub 2005 Apr 18. PMID:15978953

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-'''Plasmodium falciparum lactate dehydrogenase complexed with 2-({4-chloro-[hydroxy(methoxy)methyl]cyclohexyl}amino)ethane-1,1,2-triol'''
+===Plasmodium falciparum lactate dehydrogenase complexed with 2-({4-chloro-[hydroxy(methoxy)methyl]cyclohexyl}amino)ethane-1,1,2-triol===
-==Overview==
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-Gossypol is a di-sesquiterpene natural-product in the form of a functionalised binaphthyl and is isolated from cotton plants. The compound has long been known to exhibit anti-malarial and other biological activities. Previous studies have indicated that compounds of this type target Plasmodium falciparum lactate dehydrogenase (pfLDH), an essential enzyme for energy generation within the parasite. In this study, we report that simple naphthalene-based compounds, the core of the gossypol structure, exhibit weak inhibition of the parasite lactate dehydrogenase. Crystal structures of the complexes formed by binding of these naphthalene-based compounds to their target enzyme have been used to delineate the molecular features likely to form the gossypol binding site. Two modes of binding are observed: one overlapping the pyruvate but not the co-factor site, the other bridging the binding sites for the co-factor nicontinamide group and pyruvate substrate. This latter site encompasses molecular features unique to Plasmodium forms of LDH and is likely to represent the mode of binding for gossypol derivatives that show selectivity for the parasite enzymes. We also report a substrate analogue that unexpectedly binds within the adenine pocket of the co-factor groove. Although these core pharmacophore-like molecules only exhibit low levels of inhibitory activity, these molecular snapshots provide a rational basis for renewed structure-based development of naphthalene-based compounds as anti-malarial agents.
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 ==About this Structure==
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