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Homology modeling and molecular docking study of translationally controlled tumor protein and artemisinin
Jinsun Chae1, Inhee Choi, Choonmi Kim
1College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.
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 of Plasmodium 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 of PfTCTP. Study of the docking of artemisinin with heme, and subsequently with PfTCTP, was carried out to verify the above hypothesis on the basis of structural interactions. The three dimensional (3D) structure of PfTCTP was built by homology modeling, using the NMR structure of the TCTP of Schizosaccharomyces 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 and PfTCTP 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 2.6A, implying the strong possibility of an interaction between the two molecules, as proposed. When the activated form of artemisinin was docked on the PfTCTP, the C4-radical of the drug faced towards the sulfur of Cys14 within a distance of 2.48A, 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.
Insights
This study investigated how the antimalarial drug artemisinin interacts with Plasmodium falciparum TCTP (translationally controlled tumor protein). Molecular modeling confirmed artemisinin likely alkylates PfTCTP, explaining its antimalarial mechanism.
Area of Science:
- Biochemistry
- Molecular Biology
- Parasitology
Background:
- Translationally controlled tumor protein (TCTP), also known as histamine releasing factor (HRF), is a highly conserved protein across species.
- TCTP plays roles in cell growth and allergic reactions, but its precise functions require further elucidation.
- Plasmodium falciparum TCTP (PfTCTP) is a target for the antimalarial drug artemisinin, which is activated by heme.
Purpose of the Study:
- To investigate the molecular mechanism of artemisinin's antimalarial activity by studying its interaction with PfTCTP.
- To verify the hypothesis that heme-activated artemisinin alkylates PfTCTP, specifically at Cys14.
Main Methods:
- Homology modeling was used to construct the 3D structure of PfTCTP, utilizing the NMR structure of TCTP from Schizosaccharomyces pombe as a template.
- Molecular docking simulations (FlexiDock) were performed to analyze the interactions between artemisinin, heme, and the modeled PfTCTP structure.
- The quality of the PfTCTP model was assessed using secondary structure analysis, functional evaluation, and structure-checking programs.
Main Results:
- Docking simulations showed a close proximity (2.6Å) between the peroxide bond of artemisinin and the iron atom of heme, supporting their interaction.
- The activated form of artemisinin was positioned near Cys14 of PfTCTP (2.48Å), indicating a high likelihood of alkylation at this residue.
- These findings provide structural evidence for the proposed mechanism of artemisinin's action against malaria parasites.
Conclusions:
- The study confirms the proposed mechanism of artemisinin's antimalarial effect through molecular modeling.
- The findings suggest that artemisinin, upon activation by heme, alkylates PfTCTP, leading to parasite death.
- Molecular modeling offers a reliable approach to elucidate the biological activity mechanisms of drugs like artemisinin.
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