Probing the role of protein-protein interactions in citrullination using DNA encoded cyclic peptide libraries

This 4-year PhD studentship is offered in Dr Louise Walport’s Group based at the Francis Crick Institute (the Crick).

Protein citrullination is a widespread post-translational modification catalysed by a family of five enzymes, the peptidyl arginine deiminases (PADs). The conversion of arginine to citrulline causes a loss of charge that can have profound effects on protein structure and function. PAD-catalysed citrullination occurs on a wide range of proteins, including structural proteins (e.g. keratin), and those involved in gene regulation (e.g. histones).1 Dysregulation of citrullination and PAD activity has been linked to numerous diseases including rheumatoid arthritis, multiple sclerosis and various cancers, and likely plays key roles in early development and fertility. Recent evidence suggests that PAD inhibition has significant therapeutic potential.2 Despite this, the ways in which the PADs are regulated and directed towards their different substrates within the cell remains an enigma. Given the myriad roles of PADs within organisms there is a need for tailored compounds that modulate only given subsets of their catalytic activity. These compounds would provide powerful tools to dissect the individual roles of, for example, subsets of PAD4 target genes, in a way that is difficult to achieve through genetic manipulation, and in the longer term might provide the basis for pharmaceutical agents with reduced side effects.

An emerging method of drug discovery involves use of DNA-encoded libraries, which allow high-throughput screening of highly diverse compound libraries (containing up to 1013 members).3,4 The Walport lab uses one such method, an mRNA-display-based in vitro translation system incorporating genetic code reprogramming (the RaPID system), to identify potent macrocyclic peptide binders of biologically important proteins.5 These cyclic peptides are ideal molecules for developing chemical probes for challenging targets, such as the large, often featureless interfaces of protein-protein interactions (PPIs) or for gaining selectivity between closely related proteins.3

You will use the powerful RaPID system to develop cyclic peptides as tools to disrupt and interrogate PAD activity within a cell. You will design and implement a novel selection scheme to identify peptide binders of specific protein interfaces with which to make PPI inhibitors of specific PAD interactions. Peptide hits can be readily synthesised and further functionalised to develop tools that will be used to investigate the roles of these individual interactions in PAD targeting within mammalian cells.

Applications are invited from talented and enthusiastic students interested in applying the tools and methods of chemistry to the understanding of biological processes. You will benefit from being a member of a highly interdisciplinary group, allowing exposure to a wide variety of research techniques, ranging from organic chemistry and peptide synthesis, to protein crystallography and cell-based experiments.

Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2019 and will register for their PhD at one of the Crick partner universities (Imperial College London, King’s College London or UCL).

Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.

APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘APPLY NOW’ LINK ABOVE) BY 12:00 (NOON) NOVEMBER 13 2018. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.