The variant surface antigen PfEMP1 (Plasmodium falciparum erythrocyte membrane protein 1) encoded by the polymorphic multi-copy var gene family plays an important role in parasite biology and the host-parasite interactions. Sequestration and antigenic variation is an essential component in the survival and pathogenesis of Plasmodium falciparum and contributes to chronic infection. The DBLα domain of PfEMP1 is a potential target for immuno-epidemiological studies and has been visualized as a vaccine candidate against severe malaria. Specific host receptors like heparin, heparan sulphate, blood group A and complement receptor 1 have been reported to bind the DBLα domain. Although heparin has been experimentally shown to disrupt the parasite-host interaction and effectively disrupt rosetting, the binding sites for the DBLα domain and the mechanism behind heparin-mediated rosette inhibition have not been elucidated. In this study, 3D structures and epitopes of the DBLα domain in 3D7 and in two Indian isolates have been predicted and compared. We have carried out docking studies on DBLα domains with human GAG receptors (heparin and heparan sulphate) to predict the strength of association between the protein-ligand interactions. The DBLα domain structures showed extensive diversity and polymorphism in their binding sites. The docking results indicate that heparin binds more effectively with high affinity as compared to heparan sulphate with some common interacting residues. These common residues can play an important role in rosetting and will aid in the designing of inhibitors specific to the interactions between DBLα and heparin or heparan sulphate would be important in malaria treatment. Thus it may lead to the development of novel interference strategies to block red blood cell invasion and provide protection against malaria.
P. falciparum encodes PfEMP-1 which is important in pathogenicity and virulence. We have analyzed the structure of the Duffy binding like (DBLalpha) domain of var genes and predicted the antigenic sites and T and B cell epitopes which present a highly variable picture with major implications in immune interactions and vaccine design.
The X-ray crystal structures of two ciprofloxacin compounds, viz. [Cu(cfH) 2 (Cl) 2 ] Á 2MeOH Á 6H 2 O (2) and [Cu(cfH)(phen)Cl]BF 4 Á 4H 2 O (3) are reported. Complex (2) has a distorted octahedral geometry, whereas for the nitrogen adduct (3) a distorted square-pyramidal geometry is seen. Significant enhancement in the antimycobacterial activity of the copper conjugates correlates with their copper redox couples (Cu 2+ /Cu + ) probably due to its relevance to intracellular accumulations and subsequent role in generating oxidative stress.
Plasmodium falciparum synthesizes P. falciparum erythrocyte membrane protein-1 (PfEMP-1), a product of the multicopy var gene family, which localizes on the surface of infected erythrocytes. This protein plays an important role in cytoadherence and immune evasion. Comparative analysis of the molecular sequences of the DBLα domain of the var gene from different isolates of the parasite reveals variations in the number of cysteines and presence of small conserved motifs like DGEA, RGD, GAG-binding motifs. Phylogenetic analysis while highlighting the extensive diversity leads to clustered them in separate clades far apart from each other. Discriminant factor analysis of physicochemical properties of amino acid sequences revealed that the aliphatic index, isoelectric point, and instability index have more effect in deciding the variance of different isolates sequences. The origin of diverse repertoire of the DBLα domain in the parasites highlights the complexity of host-parasite relationship in the context of parasite survival.
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