1u5c
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Plasmodium falciparum lactate dehydrogenase complexed with 3,7-dihydroxynaphthalene-2-carboxylic acid and NAD+
OverviewOverview
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.
About this StructureAbout this Structure
1U5C is a Single protein structure of sequence from Plasmodium falciparum with NAD and BIK as ligands. Active as L-lactate dehydrogenase, with EC number 1.1.1.27 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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