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Directing protein modification in living systems with bifunctional molecules

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

About This PhD Project

Project Description

We welcome applications for a 4-year MRes/PhD studentship funded by EPSRC and Merck Sharp & Dohme (MSD), co-supervised by Professor Edward Tate (Imperial College London and the Francis Crick Institute) and Dr Mark Rackham (MSD).
Protein post-translational modifications (PTMs) are chemical changes to the structure of a protein after it has been made in the cell and are typically introduced and/or removed by enzymes. There are over 1000 classes of PTM in the human proteome introduced at over 1 million distinct sites on proteins. PTMs often have a profound effect on protein function and regulate all aspects of biology and underlie or represent opportunities for intervention in every type of disease. Recently, a new drug discovery paradigm has emerged whereby bifunctional molecules induce assembly of complexes which catalyse PTMs de novo, most prominently to induce ubiquitination and degradation of a target protein (so-called ‘PROTACs’), a modality recently progressed into clinical trials. Since they co-opt enzyme catalytic functions already present in cells, such drugs can deliver potent biological effects at low occupancy and at sites unrelated to protein function, overturning previous assumptions about what can be achieved with small molecules. Drawing on the deep expertise of the Tate group in the design of chemical tools to understand and exploit PTMs in living systems and the world-leading capabilities at MSD in drug discovery and development, you will design, synthesise and develop a new class of bifunctional molecules capable of inducing dramatic changes in protein function and localisation, with profound potential for manipulating biology and modulating disease outcomes.

This studentship would suit a talented and motivated chemist or chemical biologist who is passionate about research at the interface with biomedicine, and with a strong interest in studying the chemical probes they design hands-on in living systems. Applicants should have an outstanding academic background in chemistry or a closely related area and hold or expect to obtain a Master’s level qualification, with a strong interest in applying medicinal chemistry and chemical biology to living systems in a multidisciplinary project. Training will be provided in all relevant areas (synthesis, molecular cell biology, proteomics, etc.), but previous lab experience in synthetic and/or medicinal chemistry or in some aspect of biology or biochemistry would be a strong advantage. The successful applicant will undertake research at the new £170M state-of-the-art Molecular Sciences Research Hub at Imperial’s new White City Campus, and at the Tate & MSD labs at the Francis Crick Institute in central London.

Informal enquiries can be directed to:

Tate group webpage: http://www.imperial.ac.uk/tate-group/

References

Nature Commun 2020, 11, 1132;
Nature Chem Biol 2020, in press;
Nature Chemistry 2019, 11, 552-61;
Nature 2019, 575, 693;
Nature Chemistry 2018, 10, 599–606;
Nature Chemistry 2014, 6, 112-121;
Nature Commun 2014, 5, 4919

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