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PhD Studentship: Development and Application of Chemical Probes to target Protein-Protein Interactions

University of Birmingham - School of Chemistry

Qualification Type: PhD
Location: Birmingham
Funding for: UK Students
Funding amount: Fully funded studentship
Hours: Full Time
Placed On: 9th November 2023
Closes: 4th January 2024

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. The project will be supervised by Professor Andy Wilson and Professor Steve Smerdon.

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.

Funding notes:

BBSRC Midlands Integrative Biosciences Training Partnership Studentships include:

Full tuition fees (at UK rate) *

  • a tax free annual stipend (in academic year 2023-24 this was £18,622.00)**
  • a travel allowance in year 1
  • a travel / conference budget
  • a generous consumables budget
  • use of a MacBook Pro for the duration of the programme.

References:
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.
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.
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.
T. Ueda, T. Tamura, M. Kawano, K. Shiono, F. Hobor, A. J. Wilson and I. Hamachi, J. Am. Chem. Soc., 2021, 143, 4766-4774.
S. Srdanovic, M. Wolter, C. H. Trinh, C. Ottmann, S. L. Warriner and A. J. Wilson, FEBS J., 2022, 289, 5341-5358.

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