Abstract
Translationally controlled tumor protein (TCTP), also known as histamine releasing factor (HRF), is found abundantly in different eukaryotic cell types. The sequence homology of TCTP between different species is very high, belonging to the MSS4/DSS4 superfamily of proteins. TCTP is involved in both cell growth and human late allergy reaction, as well as having a calcium binding property; however, its primary biological functions remain to be clearly elucidated. In regard to many possible functions, the TCTP ofPlasmodium falciparum (Pf) is known to bind with an antimalarial agent, artemisinin, which is activated by heme. It is assumed that the endoperoxide-bridge of artemisinin is opened up by heme to form a free radical, which then eventually alkylates, probably to the Cys14 ofPfTCTP. Study of the docking of artemisinin with heme, and subsequently withPfTCTP, was carried out to verify the above hypothesis on the basis of structural interactions. The three dimensional (3D) structure ofPfTCTP was built by homology modeling, using the NMR structure of the TCTP ofSchizosaccharomyces pombe as a template. The quality of the model was examined based on its secondary structure and biological function, as well as with the use of structure evaluating programs. The interactions between artemisinin, heme andPfTCTP were then studied using the docking program, FlexiDock. The center of the peroxide bond of artemisinin and the Fe of heme were docked within a short distance of 2.6Å, implying the strong possibility of an interaction between the two molecules, as proposed. When the activated form of artemisinin was docked on thePfTCTP, the C4-radical of the drug faced towards the sulfur of Cys14 within a distance of 2.48Å, again suggesting the possibility of alkylation having occurred. These results confirm the proposed mechanism of the antimalarial effect of artemisinin, which will provide a reliable method for establishing the mechanism of its biological activity using a molecular modeling study.
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Chae, J., Choi, I. & Kim, C. Homology modeling and molecular docking study of translationally controlled tumor protein and artemisinin. Arch Pharm Res 29, 50–58 (2006). https://doi.org/10.1007/BF02977468
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DOI: https://doi.org/10.1007/BF02977468