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Structural characterisation of the human equilibrative nucleoside transporter, a target for cancer, malaria and AIDS.

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  • Full or part time
    Dr S Harborne
    Prof A Goldman
    Prof P J F Henderson
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Our goal is to understand the structure and mechanism of equilibrative nucleoside transporters (ENTs), a key family of membrane protein transporters important in cancer, malaria and AIDS. Integral membrane proteins comprise approximately 30% of the human proteome, representing a significant target for drug discovery efforts. Despite this, we currently have very little structural information about them: only ≈2% of the protein structures solved to date represent novel membrane protein families, and even fewer are eukaryotic proteins.

Primarily the focus of the project will be on the expression, purification, stabilisation and structural characterisation of ENTs by X-ray crystallography and cryo-EM. The project will allow training in a broad range of structural and biochemical techniques applied to membrane proteins; such as:
- insect and mammalian cell culture
- radioactive binding assays
- thermostability assays
- analytical size exclusion
- X-ray crystallography
- cryo-EM
- molecular dynamics simulations

ENTs represent an important class of protein for pharmacological treatment of cancer (1), protozoan parasites such as Plasmodium falciparum (malaria) (2) and viral diseases such as AIDS (3). Under physiological circumstances, the ENTs are involved in the uptake of nucleosides and nucleobases into cells, salvaging important building-blocks for the synthesis of DNA and RNA (3). ENTs are ubiquitously expressed across human tissues (3), and their function is particularly important in erythrocytes, leukocytes, bone marrow cells and some cells in the brain, which are deficient for de-novo synthesis of nucleotides (3). Furthermore, ENTs directly influence the concentration of adenosine available to cell surface receptors (3) and so processes such as coronary blood flow, myocardial O2 supply–demand balance, inflammation and neurotransmission.

The project will be carried out between the Astbury Centre for Structural Biology at Leeds University and our industrial collaborators at Novartis in Switzerland. The Astbury Centre for Structural Biology is one of the most diverse, multidisciplinary structural biology centres in the world. It encompasses 75 groups in Physics, Chemistry and Biological Sciences. With a recent £17 million investment by the University of Leeds and further investment by the Wellcome Trust and BBSRC in structural molecular biology the project will have access to world leading state of the art membrane protein production, X-ray crystallography and cryo-EM facilities.

Funding Notes

Fully funded BBSRC iCASE studentship, providing UK/EU level fees plus a stipend (£14,296) for 4 years. EU candidates must have resided in the UK for three years prior to the start of the PhD to be eligible for full support; without evidence of residency the studentship will only provide fees and no stipend. Non-UK/EU candidates are not eligible. Candidates should have or be expecting a 2.1 or above at undergraduate level in a relevant subject. If English is not your first language you will be required to meet our English language requirements. The start date will be Oct 2017.

References

References:
1. T. Oguri et al., Cancer Lett. 256, 112–119 (2007).
2. R. Deniskin et al., Int. J. Parasitol. Drugs Drug Resist. 6, 1–11 (2016).
3. J. D. Young et al., Xenobiotica. 38, 995–1021 (2008).

Important papers from the lab:
Li, K.-M., Wilkinson, C., Kellosalo, J., Tsai, J.-Y., Kajander, T. S., Sun, Y-J. & Goldman, A. Membrane pyrophosphatases from Thermotoga maritima and Vigna radiata suggest a conserved coupling mechanism. Nat. Commun. (2016).
Kellosalo, J., Kajander, T., Kogan, K., Pokharel, K. & Goldman, A. The Structure and Catalytic Cycle of a Sodium-Pumping Pyrophosphatase. Science 337, 473-476 (2012).
Kajander, T., Lehtinen, M. J., Hyvärinen, S., Bhattacharjee, A., Leung, E., Isenman, D. E., Meri, S., Goldman, A. & Jokiranta, S. T. Dual interaction of factor H with C3d and glycosaminoglycans in host-nonhost discrimination by complement. Proc. Natl. Acad. Sci U.S.A., 108, 2897-2902 (2011).

How good is research at University of Leeds in Biological Sciences?

FTE Category A staff submitted: 60.90

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