MSc by Research: Identifying and studying interacting proteins that are “glue-able” to small molecules

About the Project

Recent advances from the Ciulli Lab and others have contributed to the establishment of a transformative new modality of chemical intervention into biological system – one that moves beyond the state-of-the-art. Instead of blocking a target protein with conventional inhibitors, we are now designing and studying “tailored” molecules, multi-specific in concept and function, that bring two or more proteins together by forming a ternary (or higher order) complex. We have shown that specific molecular recognition features of such ternary complexes, such as their cooperativity and thermodynamic and kinetic stability, are a key feature of their “molecular glue” activity, and drive fast and effective induce proximity-driven chemistries. For degrader molecules that co-opt E3 ligases to target protein, this specifically relates to protein ubiquitylation and subsequent proteasomal degradation. We are beginning to understand the rules of how to design and study this new class of molecules in order to best re-wire specific downstream signalling events, with profound biological consequences and attractive therapeutic potential.

Our research in this area takes a multidisciplinary approach including organic and medicinal chemistryand computational tools to design and achieve desired molecules; biophysics and structural biology, including the use of cryo-electron microscopy, to study binary and ternary complexes in solution and reveal their structural and dynamic interactions; and chemical biology, biochemistry, proteomics and cell biologyto study the cellular impact of our small molecules in relevant cellular systems – for example cancer cells sensitive to the knockdown or other modification of the protein target in question.

The key long-term research questions of the project will be: how to best identify protein pairs that have intrinsically basal affinity and surface complementarity, and understand how to use that information to accelerate the discovery and more rational design of molecular glues. A one-year Master project would typically fit as part of an on-going project and research interest of the Lab. Importantly; it can be tailored to the student specific interests and motivations.

The student will join a vibrant research group led by Professor Ciulli who is the Director of the Centre for Targeted Protein Degradation and has extensive experience of supervising students. The student will benefit from access to excellent expertise, facilities, and support that will prove invaluable for their scientific and professional development. The group and wider CeTPD have lot of collaborations with industry which will also advance the student’s personal and professional development beyond what is possible through an academic-only Master project.

If you are interested in joining the lab and contributing to our science in this exciting new area, to learn more about our work and to discuss potential opportunities, do not hesitate to get in touch with Alessio (a.ciulli@dundee.ac.uk).

Recent references

Liu, X., Ciulli, A.*
Proximity-Based Modalities for Biology and Medicine
ACS Cent. Sci. 2023, 9 (7), 1269–1284

Hsia, O. et al.
Targeted protein degradation via intramolecular bivalent glues.
Nature 2024, 627 (8002), 204–211.

Kroupova, A. et al.
Design of a Cereblon construct for crystallographic and biophysical studies of protein degraders.
Nat Commun. 2024 Oct 15;15(1):8885.

Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research. We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education.

Please see our website for further details on the programme and how to apply:
Life Sciences MSc by Research MSc by Research (Postgraduate) : Study : University of Dundee

Please note before submitting your application that you must list your top three project choices in the Research Proposal section of the application form.

When you complete your application form, you should include your top 3 project choices, 2 letters of reference, uploaded under "Other Information" > "Supporting documents" and a personal statement. Failure to do so will delay your application.

Please note when submitting an application, please note our intake deadlines on the ‘how to apply’ section of our website