Project Outline

Transient protein-protein interactions (PPIs) control all cellular processes relevant to health and disease. Thus, a major problem in life-sciences research is to understand and manipulate PPIs with molecular and temporal resolution. Addressing this challenge will illuminate our understanding of disease development e.g. cell signalling in cancer and provide starting points for drug-discovery. However, methods to interrogate and manipulate PPIs are not well established. Moreover, intrinsically disordered regions – segments of protein with no fixed structure – that undergo disorder-to-order transitions upon formation of the PPI, compound this challenge.

A number of approaches to modulation of PPIs including competitive inhibition, stabilization and allosteric inhibition can be envisioned. Informed by structural and mechanistic understanding of the interactions between IDRs and their client proteins,1,2 our group has developed a number of enabling methods that include computational methods,3 constrained peptides,1 and covalent inhibitors.4 In this PhD project the student will extend and apply these methods to focussed PPI modulator projects. Relevant targets include: HIF-1α/p300,2 interactions of 14-3-3 proteins,5 (all oncology), and JMJD5/client interactions. A range of methods appropriate to the target will be employed including: computational prediction, peptide chemistry, novel fragment-screening technologies, development of new covalent warheads, biophysics and structural-molecular biology. This will allow the design, synthesis and testing of candidate PPI modulators to discover selective and cell-permeable modulator of the target PPI and ultimately chemical probes.

You will join a vibrant, diverse and group of researchers to gain skills and knowledge in chemical and structural biology in its broadest sense, and, participate in our wider collaborative research.

References

1. J. A. Miles, D. J. Yeo, P. Rowell, S. Rodriguez-Marin, C. M. Pask, S. L. Warriner, T. A. Edwards and A. J. Wilson, Chem. Sci., 2016, 7, 3694-3702.
2. F. Hóbor, Z. Hegedüs, A. A. Ibarra, V. L. Petrovicz, G. J. Bartlett, R. B. Sessions, A. J. Wilson and T. A. Edwards, RSC. Chem. Biol., 2022, 3, 592-603.
3. S. Celis, F. Hobor, T. James, G. J. Bartlett, A. A. Ibarra, D. K. Shoemark, Z. Hegedüs, K. Hetherington, D. N. Woolfson, R. B. Sessions, T. A. Edwards, D. M. Andrews, A. Nelson and A. J. Wilson, Chem. Sci., 2021, 12, 4753-4762.
4. T. Ueda, T. Tamura, M. Kawano, K. Shiono, F. Hobor, A. J. Wilson and I. Hamachi, J. Am. Chem. Soc., 2021, 143, 4766-4774.
5. S. Srdanovic, M. Wolter, C. H. Trinh, C. Ottmann, S. L. Warriner and A. J. Wilson, FEBS J., 2022, 289, 5341-5358.

Techniques

This interdisciplinary project described involves chemical synthesis, molecular biology and recombinant protein expression, biophysical/biochemical assay development and implementation, structural biology and cell assays as appropriate.