Elucidating the structure of Malaria gyrase - MSc bioinformatics project

biological background

Malaria is still an ongoing problem worldwide. The deadliest form of malaria is caused by the Plasmodium falciparum parasite which affects millions of people and kills over 500,000 every year according to the WHO. The parasite contains an organelle called the apicoplast inside which there is a special topoisomerase - DNA gyrase. This enzyme is also present in bacteria and widely used as an antibacterial drug target because it induces double strand DNA breaks during its mechanism of action and popular antibacterial drugs cause the enzyme to release these breaks, killing the cell. In theory then, apicoplast gyrase should be a good target for novel antimalarial drugs. To understand if this is the case we need to characterise this gyrase but despite similarities to bacterial gyrases, Plasmodium falciparum gyrase remains unknown and so far nobody has succeeded in expressing the protein and the reasons for those problems are unknown.

bacterial gyrase crystal structure

the project

In this project, we want to computationally understand the structural features of Plasmodium gyrase and devise strategies to be the first in the world to experimentally express it. Many bacterial gyrases have a known structure and we already understand how they work. Plasmodium gyrase is a relative of these but cannot, to date, be expressed and purified. We hypothesize that it is due to an additional domain in this protein that is intrinsically disordered and folds-upon-binding another protein. In its disordered state, the protein is quickly degraded when attempted to be expressed. To solve this problem, we want to first investigate the architecture differences the Plasmodium gyrase and bacterial gyrases to better learn how different they are. Once we achieve this, we will use a variety of bioinformatic techniques to characterize the novel regions and using state-of-the art molecular simulations, as well as deep learning-based tools find mutations or binding partners that would help us express this protein.

The wet-lab work informed by this project is going to be performed in the Heddle Lab. Hence, this project has immediate practical consequences and a significant scientific and medical potential! It is an opportunity for interdisciplinary work in an international research team.

the lab

The project will be held at the Małopolska Centre of Biotechnology between the labs of Structural and Functional Genomics (Tomasz Kościółek) and Bionano and Biochemistry Lab (Jonathan Heddle).

Interested students, please inquire via email, with Plasmodium gyrase as the subject line, to work@tomaszlab.org

We are committed to equal opportunities and will not discriminate anyone on the basis of: nationality, age, sex, race, disability, religion, sexual orientation and pregnancy/maternity.