Skip to Main content Skip to Navigation
Theses

Study of structural and functional dynamics of translocator protein, a new target for treatment of malaria

Abstract : Despite availability of different drugs, malaria remains a serious health challenge in tropical countries, and is rapidly making inroads in the countries with temperate climate. To compound the problem, resistance to the antimalarial drugs by the Plasmodial parasite has been documented in many instances, underscoring the need for novel therapeutic approaches for the disease. However, discovery of involvement of a transmembrane protein Translocator protein (TSPO) in the Plasmodium-infected erythrocytes showed the potential of this protein as a target for novel antimalarial drugs. TSPO is an 18 kDa transmembrane protein found in various organelles of cell and involved in variety of processes, including steroidogenesis and cholesterol transport, tetrapyrrole transport/catalysis, erythropoiesis. apoptosis, response to stress to name a few. As a result, it is also involved in various diseases apart from malaria, and is considered a potential drug target. Though recent studies on its atomic structure provided some interesting insights into the structure, several questions on the structure-dynamics-function relationship of TSPO remained unanswered. In this thesis, we attempted to answer some of these questions using various bioinformatics and molecular modelling approaches. We describe how does the ligand PK11195 influence the dynamics of TSPO using all-atom molecular dynamics simulations, and how does PK11195 itself behave in complex with TSPO. We also studied different aspects of TSPO oligomerization using coarse-grained molecular dynamics simulations, and explored how do mammalian TSPO dynamics compare with those of bacterial homologs. Ultimately, we attempted to make a comprehensive comparison between the two paralogs of TSPO in mammals, TSPO1 and TSPO2, from sequence, structural as well as phylogenetic perspectives. Our results give interesting insights into the structure-dynamics-function relationships of TSPO, and pave way to some new hypotheses on the same, which could be exploited to develop new generation of antimalarial drugs that target TSPO.
Complete list of metadatas

Cited literature [525 references]  Display  Hide  Download

https://tel.archives-ouvertes.fr/tel-02477321
Contributor : Abes Star :  Contact
Submitted on : Thursday, February 13, 2020 - 12:04:08 PM
Last modification on : Friday, September 11, 2020 - 3:09:31 AM
Long-term archiving on: : Thursday, May 14, 2020 - 2:10:47 PM

File

2019lare0016_RMrao.pdf
Version validated by the jury (STAR)

Identifiers

  • HAL Id : tel-02477321, version 1

Citation

Rajas Mallenahalli Rao. Study of structural and functional dynamics of translocator protein, a new target for treatment of malaria. Bioinformatics [q-bio.QM]. Université de la Réunion, 2019. English. ⟨NNT : 2019LARE0016⟩. ⟨tel-02477321⟩

Share

Metrics

Record views

108

Files downloads

49