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Chemical biology approaches to study the ubiquitin system

  • Full or part time
    Dr K Rittinger
  • Application Deadline
    Tuesday, November 12, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

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

Protein ubiquitination is a reversible post-translational modification used to regulate a large variety of cellular processes including protein degradation, DNA repair, signalling processes and the host immune responses. Not surprisingly, dysregulation of the ubiquitin system is associated with a wide range of diseases including cancer, neurodegeneration, or immune and infectious diseases. Although there is a lot of interest in targeting the ubiquitin system for therapeutic purposes, progress in this area has been slow in part because protein ubiquitination involves multiple protein-protein interactions that are more challenging to target than active-site pockets.

Ubiquitination is mediated by a sequential cascade of E1 ubiquitin activating, E2 conjugating and E3 ligating enzymes. Proteins can be modified with single ubiquitin molecules or poly-ubiquitin chains of different topologies, the nature of which determines the physiological outcome of the modification. E3 ligases are the key players in the ubiquitination process and provide substrate specificity and in some cases also determine chain topology. They can be divided into 3 different subfamilies that differ in the mechanism of ubiquitin transfer to the substrate: RING-type E3 ligases mediate the direct transfer of ubiquitin from the E2 conjugating enzyme onto the substrate, whereas HECT and RBR-type E3s form a thioester intermediate with ubiquitin before its subsequent transfer onto the substrate.

We have recently developed a fragment-based covalent ligand screening method to discover lead compounds against active site cysteine–containing E3 ubiquitin ligases. Screening this novel library against the RBR E3 ligase HOIP identified a compound selective for HOIP, which we are now improving into a cell-permeable inhibitor that can be used to study HOIP function in a physiological context. In contrast, RING-type E3 ligases do not contain an active site cysteine and hence cannot be targeted using the same approach. This PhD project is aimed at investigating if the activity of RING-type E3s can be targeted by interfering with ligase-substrate interactions. Specifically, we will focus on TRIM E3 ligases to complement ongoing structural and functional studies on this large E3 ligase family. This PhD project will apply fragment-based approaches, including emerging novel covalent warheads, to target the different types of substrate binding domains that are found within the TRIM family. In parallel, there is the possibility to work closely with structural biologists within the group to use chemical approaches to develop molecules that can stabilise difficult to trap multi-protein complexes or conformations and thereby enable otherwise challenging structural studies.

This project will be carried out in close collaboration with GSK and will be jointly supervised with Dr. Jacob Bush, GSK.

Candidate background
This project is ideally suited for candidates with a background in chemistry and a strong interest in chemical biology and the application of chemistry to the study of protein structure and function. This is a multi-disciplinary project and the candidate will receive training in chemical biology approaches, including synthetic chemistry, fragment screening, medicinal chemistry and protein mass spectrometry, alongside modern biochemical and structural techniques, including but not limited to protein expression/purification, characterisation of protein-protein interactions by a wide range of biophysical techniques (ITC, Octet/Biacore, MALLS, fluorescence spectroscopy, SAXS), and structural characterisation of protein-fragment complexes by X-ray crystallography.

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 2020 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) 13 NOVEMBER 2019. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.

Funding Notes

Successful applicants will be awarded a non-taxable annual stipend of £22,000 plus payment of university tuition fees. Students of all nationalities are eligible to apply.

References

1. Johansson, H., Tsai, Y.-C. I., Fantom, K., Chung, C.-W., Kümper, S., Martino, L., . . . Rittinger, K. (2019)
Fragment-based covalent ligand screening enables rapid discovery of inhibitors for the RBR E3 ubiquitin ligase HOIP.
Journal of the American Chemical Society 141: 2703-2712. PubMed abstract
2. Koliopoulos, M. G., Lethier, M., van der Veen, A. G., Haubrich, K., Hennig, J., Kowalinski, E., . . . Rittinger, K. (2018)
Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition.
Nature Communications 9: 1820. PubMed abstract
3. Esposito, D., Koliopoulos, M. G. and Rittinger, K. (2017)
Structural determinants of TRIM protein function.
Biochemical Society Transactions 45: 183-191. PubMed abstract
4. Hatakeyama, S. (2017)
TRIM family proteins: Roles in autophagy, immunity, and carcinogenesis.
Trends in Biochemical Sciences 42: 297-311. PubMed abstract
5. Huang, X. and Dixit, V. M. (2016)
Drugging the undruggables: exploring the ubiquitin system for drug development.
Cell Research 26: 484-498. PubMed abstract



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