Dataset Information

Structure of the 40S ribosomal subunit of Plasmodium falciparum by homology and de novo modeling.

ABSTRACT: Generation of three dimensional structures of macromolecules using in silico structural modeling technologies such as homology and de novo modeling has improved dramatically and increased the speed by which tertiary structures of organisms can be generated. This is especially the case if a homologous crystal structure is already available. High-resolution structures can be rapidly created using only their sequence information as input, a process that has the potential to increase the speed of scientific discovery. In this study, homology modeling and structure prediction tools such as RNA123 and SWISS-MODEL were used to generate the 40S ribosomal subunit from Plasmodium falciparum. This structure was modeled using the published crystal structure from Tetrahymena thermophila, a homologous eukaryote. In the absence of the Plasmodium falciparum 40S ribosomal crystal structure, the model accurately depicts a global topology, secondary and tertiary connections, and gives an overall root mean square deviation (RMSD) value of 3.9 Å relative to the template?s crystal structure. Deviations are somewhat larger in areas with no homology between the templates. These results demonstrate that this approach has the power to identify motifs of interest in RNA and identify potential drug targets for macromolecules whose crystal structures are unknown. The results also show the utility of RNA homology modeling software for structure determination and lay the groundwork for applying this approach to larger and more complex eukaryotic ribosomes and other RNA-protein complexes. Structures generated from this study can be used in in silico screening experiments and lead to the determination of structures for targets/hit complexes.

SUBMITTER: Mwangi HN

PROVIDER: S-EPMC5237758 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Structure of the 40S ribosomal subunit of Plasmodium falciparum by homology and de novo modeling.

Mwangi Harrison Ndung'u HN Wagacha Peter P Mathenge Peterson P Sijenyi Fredrick F Mulaa Francis F

Acta pharmaceutica Sinica. B 20161207 1

Generation of three dimensional structures of macromolecules using in silico structural modeling technologies such as homology and de novo modeling has improved dramatically and increased the speed by which tertiary structures of organisms can be generated. This is especially the case if a homologous crystal structure is already available. High-resolution structures can be rapidly created using only their sequence information as input, a process that has the potential to increase t ...[more]

PMID: 28119814

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Project description:Immunodeficient mouse-human chimeras provide a powerful approach to study host specific pathogens like Plasmodium (P.) falciparum that causes human malaria. Existing mouse models of P. falciparum infection require repeated injections of human red blood cells (RBCs). In addition, clodronate lipsomes and anti-neutrophil antibodies are injected to suppress the clearance of human RBCs by the residual immune system of the immunodeficient mice. Engraftment of NOD-scid Il2rg-/- mice with human hematopoietic stem cells leads to reconstitution of human immune cells. Although human B cell reconstitution is robust and T cell reconstitution is reasonable in the recipient mice, human RBC reconstitution is generally poor or undetectable. The poor reconstitution is mainly the result of a deficiency of appropriate human cytokines that are necessary for the development and maintenance of these cell lineages. Delivery of plasmid DNA encoding human erythropoietin and interleukin-3 into humanized mice by hydrodynamic tail-vein injection resulted in significantly enhanced reconstitution of erythrocytes. With this improved humanized mouse, here we show that P. falciparum infects de novo generated human RBCs, develops into schizonts and causes successive reinvasion. We also show that different parasite strains exhibit variation in their ability to infect these humanized mice. Parasites could be detected by nested PCR in the blood samples of humanized mice infected with P. falciparum K1 and HB3 strains for 3 cycles, whereas in other strains such as 3D7, DD2, 7G8, FCR3 and W2mef parasites could only be detected for 1 cycle. In vivo adaptation of K1 strain further improves the infection efficiency and parasites can be detected by microscopy for 3 cycles. The parasitemia ranges between 0.13 and 0.25% at the first cycle of infection, falls between 0.08 and 0.15% at the second cycle, and drops to barely detectable levels at the third cycle of infection. Compared to existing mouse models, our model generates human RBCs de novo and does not require the treatment of mice with immunomodulators.

Dataset Information

Structure of the 40S ribosomal subunit of Plasmodium falciparum by homology and de novo modeling.

Publications

Structure of the 40S ribosomal subunit of <i>Plasmodium falciparum</i> by homology and <i>de novo</i> modeling.

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