PROtealysis TArgeting Chimeras, also designated PROTACs, are bifunctional molecules composed of two protein ligands connected by a linker. The ligand on one side binds to the E3-ubiquitin ligase, which targets a protein for degradation, while the other ligand binds the unwanted proteins that needs to be removed from the cell. Since PROTACs had first been described in 2001, the technology has been applied to an increasing range of targets, with the first molecules now in clinical trials.
All PROTACs are based on known ligands for an E3-ligase on one side, in many cases, the Von Hippel-Lindau tumor suppressor (VHL) connected to a known or novel ligand for the target protein. However, only recently, it has become clear that the length and chemistry of the linker, in most cases composed of polyethylene glycols, or alkyls, alkynes or triazoles, plays a major role in the biological activity of the PROTAC compound. With a virtually unlimited number of potential linkers, new computational methods are needed to guide and support the development of new PROTACs.
In this project, the student will develop and validate new molecular modelling tools for linker design that use the structures of the VHL ligase and the target protein in combination with empirical rules derived from successful linkers. These tools will initially be tested and validated using one well-established PROTACs model system, VHL bound to the human bromodomain 4 (Brd4), a major target for cancer therapies, where crystals structures of the ternary VHL-PROTAC-Brd4 complex have been determined. New compounds will be synthesized by our collaborators at Durham University and Newcastle University and then validated using a wide range of biochemical and biophysical techniques. The validation includes the structure determination by X-ray crystallography and/or cryo Electron Microscopy in collaboration with MoSMed students involved in the project. After the proof-of principle experiments we will apply and further develop the methods on a number of proteins that are currently targeted in the research groups involved in this project.
Please refer to the MoSMed webpage for full details of the project PhD Openings | MoSMed CDT | Newcastle University (ncl.ac.uk).
Within the MoSMed CDT we are committed to building a diverse community based on excellence and commitment. To that end in our recruitment of Doctoral Researchers we welcome applications from outstanding candidates of all backgrounds regardless of ethnicity, disability, gender identity, sexual orientation and will consider all applications equally based on merit.
How to Apply
For full details on how to apply please refer to the MoSMed webpage: Durham | MoSMed CDT | Newcastle University (ncl.ac.uk)