PhD Studentship: Understanding and Controlling β-strand Mediated PPIs Using Bespoke Chemical Modifications

Intrinsically disordered regions (IDRs)[1], are ubiquitous stretches of protein that do not adopt a stable structure, are a major class of protein structure found in all living organisms, and, are predicted to be present in around a third of eukaryotic proteins. Crucially, IDRs are important and overrepresented in key signaling and disease pathways, spanning cancer to disorders of protein aggregation.

This PhD studentship will exploit peptidomimetic design[2-4] to develop chemical probes that can inhibit post-translation modification of proteins by small ubiquitin-related modifier (SUMO). SUMOylation regulates multiple cellular processes including transcription, replication, and DNA repair. SUMO interacting motifs (SIMs) play an important role in reading, writing and erasing SUMO. SIMs recognize SUMO through non-covalent interaction in a β-strand conformation and are typically found within intrinsically disordered regions of proteins[5]. We will apply a state of the art combination of peptide and protein chemistry,[6, 7] fragment based ligand discovery methods[3, 4] and advanced Nuclear Magnetic Resonance (NMR) experiments to identify and characterize chemical probes for a series of SIMS relevant to aggregation and DNA damage.

You will join a vibrant, diverse and group of researchers to gain skills and knowledge in chemical biology in its broadest sense, and, participate in our wider collaborative research. Ultimately, development of SIM/SUMO chemical probes be crucial in unravelling the “SUMO code”, and, will establish a platform to identify modulators of IDRs/IDPs and contribute to a systematic understanding of intrinsic disorder in β-strand mediated PPIs

Keywords: protein-protein interactions, intrinsically disordered proteins, chemical biology, peptidomimetic chemistry

Applications will be considered on an ongoing basis until a suitable candidate has accepted an offer. Applicants should contact Prof Andy Wilson (a.j.wilson.1@bham.ac.uk) for informal inquiries, and before applying (with a CV and cover letter summarizing your research interests and previous experience).

References:

1. P. E. Wright and H. J. Dyson, Nat. Rev. Mol. Cell Biol., 2015, 16, 18-29.
2. A. A. Ibarra, G. J. Bartlett, Z. Hegedüs, S. Dutt, F. Hobor, K. A. Horner, K. Hetherington, K. Spence, A. Nelson, T. A. Edwards, D. N. Woolfson, R. B. Sessions and A. J. Wilson, ACS Chem. Biol., 2019, 14, 2252-2263.
3. E. E. Cawood, N. Guthertz, J. S. Ebo, T. K. Karamanos, S. E. Radford and A. J. Wilson, J. Am. Chem. Soc., 2020, 142, 20845-20854.
4. Z. Hegedüs, F. Hóbor, D. K. Shoemark, S. Celis, L.-Y. Lian, C. H. Trinh, R. B. Sessions, T. A. Edwards and A. J. Wilson, Chem. Sci., 2021, 12, 2286-2293.
5. J. R. Gareau and C. D. Lima, Nat. Rev. Mol. Cell Biol., 2010, 11, 861-871.
6. J. E. Horne, M. Walko, A. N. Calabrese, M. A. Levenstein, D. J. Brockwell, N. Kapur, A. J. Wilson and S. E. Radford, Angew. Chem. Int. Ed., 2018, 57, 16688-16692.
7. S. J. Bunce, Y. Wang, K. L. Stewart, A. E. Ashcroft, S. E. Radford, C. K. Hall and A. J. Wilson, Sci. Adv., 2019, 5, eaav8216.

Advert information