Structural and biophysical characterisation of S6K2
Around 41,000 people are diagnosed with lung cancer in the UK every year. Of these 15% are small cell lung cancer (SCLC) and, despite initial sensitivity to treatment, the overall five year survival is 5%. The upregulation of anti-apoptotic proteins is a key feature in cancer development and, in particular for SCLC, is linked to resistance to therapy. It has been recently shown that fibroblast growth factor 2 (FGF-2) is necessary for SCLC cell proliferation and the p70 ribosomal protein S6 kinases 2 (S6K2) plays an important role in the aberrant growth response of SCLC cells (Pardo, O.E., et al. Oncogene, 2001). In the attempt to find new therapeutic approaches, targeting enzymes like S6K2, that regulate post-translational modifications, may provide a novel and efficient way to silence pro-survival signalling mechanisms in cancer. Due to the relative lack of success of small-molecule kinase inhibitors, a more appropriate way to modulate S6K2 activity could be to develop protein–protein interaction inhibitors. However, the rational design of selective therapeutics requires a mechanistic understanding of protein function and structural data.
This PhD project will focus on unravelling the molecular mechanism of S6K2 (RPS6KB2) signalling pathway. In particular the aim is to characterize S6K2 protein-protein interactions and not redundant with its closely related isoform S6K1 (Roy, R., et al. Nucleic Acids Res, 2014). At the moment there is a complete lack of biochemical and structural information about S6K2. Using a range of biophysical and biochemical techniques we aim to characterize S6K2 protein complexes and ultimately solve their crystal structures.
The successful candidate will develop skills in recombinant protein expression, protein purification, structural biology (SAXS, X-RAY), biochemical and biophysical characterisation (ITC, MST, fluorescence spectroscopy and SPR). This project will be integrated with other projects in our group focusing on regulation of kinases in signalling networks and it is anticipated that the student will also develop multidisciplinary skills, in collaboration with cell biologists in the Molecular and Cellular Biosciences Research Group of the School of Biological Sciences at the University of Essex.
There is no funding attached to this project, it is for self-funded students only
Applications should be submitted electronically by 1 June 2016
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FTE Category A staff submitted: 23.00
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