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Journal of Biological Sciences

Year: 2017  |  Volume: 17  |  Issue: 8  |  Page No.: 369 - 380

Structure and Molecular Dynamic Regulation of FKBP35 from Plasmodium knowlesi by Structural Homology Modeling and Electron Microscopy

Jovi Silvester, Herman Umbau Anak Lindang, Lee Ping Chin, Lau Tiek Ying and Cahyo Budiman


Background and Objective: The 35 kDa FK506-binding proteins (FKBP35) of plasmodium parasite is a member of peptidyl proly cis-trans isomerase consisting of FK506-binding domain (FKBD) and tetratricopeptide repeat domain (TPRD). A comprehensive understanding of structure and function relationship of this protein is needed as a platform for development of novel antimalarial drugs with no resistance effect. However, structural study of full-length FKBP35 is hampered by some issues on molecular size and dynamic due to its structural flexibility. Therefore, this study aimed to analyze full-length structure of FKBP35 from Plasmodium knowlesi (Pk FKBP35) and determine its dynamics using structural homology modeling and a transmission electron microscope (TEM). Methodology: Structural homology modeling was constructed using SWISS-MODEL and further validated using RAMPAGE, Global model quality estimation (GMQE), QMEAN statistical parameters and VERIFY3D. For electron microscopy analysis, purified Pk FKBP35 was placed on EM grid, negatively stained using 2% uranyl acetate and recorded under TEM. The image was then processed using ImageJ to classify the molecular shape of Pk FKBP35 based on circularity index. Flexibility analysis was conducted under PredyFlexy web server. Result: The 3D model of Pk FKBP35 was successfully built based on the template of 1p5q. The structure consists of 6 β-sheet and 10 α-helix secondary structures that dominates FKBD and TPRD, respectively, with high similarity to the domains of its homologous from P. falciparum and P. vivax. Negatively stained electron micrograph showed that Pk FKBP35 assumes in three conformations of elongated, hook and circular shapes, with preference conformation being circular shapes (72%). Meanwhile, flexibility prediction demonstrated that FKBD region is more flexible than TPRD. Conclusion: Three conformations concluded that Pk FKBP35 is a dynamic protein due to its flexibility properties. This dynamic might be important for acquiring the substrates. FKBD was found to modulate the flexibility of Pk FKBP35, probably due to the functional role of this catalytic domain and structurally dominated by β-sheet structure, which is more flexible than α-helix structure. Further, 3D model of Pk FKBP35 also suggested that the linker between the domains might involve in the structural dynamic.

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