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A fragment-based approach to identify protein-protein interaction inhibitors of Shelterin complex assembly

  • Full or part time
    Prof I Collins
    Dr S Guettler
    Dr S Hoelder
  • Application Deadline
    Sunday, November 17, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

About This PhD Project

Project Description

The Institute of Cancer Research, London, is one of the world’s most influential cancer research institutes. We are committed to attracting and developing the best minds in the world to join us in our mission—to make the discoveries that defeat cancer.
The ends of our linear chromosomes, the telomeres, are decorated by a multi-protein complex known as Shelterin. The Shelterin complex protects telomeres, which resemble DNA breaks, by averting an illicit telomeric DNA damage response which would threaten genomic integrity. The Shelterin complex further participates in regulating telomere length. This project aims to take the first steps in developing novel chemical tools to probe the function of Shelterin complex components. Specifically, the project will identify small molecule fragments that bind to globular domains in components of the Shelterin complex, using a combination of differential scanning fluorimetry and ligand-observed NMR methods. Fragment binding will be validated by orthogonal biophysical techniques, and the fragment binding sites located and characterised in detail using protein-observed NMR and, if possible, X-ray crystallography. The fragment-protein interaction affinities for the hits will be measured using protein-observed NMR and ITC, and early structure-activity relationship studies will be carried out by purchase or chemical synthesis of close analogues. The results of this study will be a well-understood series of fragment binders suitable for progression through medicinal chemistry to develop potent inhibitors of the protein-protein interactions in the Shelterin complex, as tool compounds to probe the roles of Shelterin in telomere biology.

For general information on activities in the host laboratories, please visit:
http://www.icr.ac.uk/our-research/researchers-and-teams/professor-ian-collins
http://www.icr.ac.uk/our-research/researchers-and-teams/sebastian-guettler
http://www.sguettlerlab.org

Chemical biology
Fragment screening
Protein-protein interactions
Biophysics
Protein biochemistry
Structural biology

Funding Notes

Students receive an annual stipend, currently £21,000 per annum, as well as having tuition fees (both UK/EU and overseas) and project costs paid for the four-year duration. We are open to applications from any eligible candidates and are committed to attracting and developing the best minds in the world.
See icr.ac.uk/phds to apply
Applications close 11:55pm UK time on Sunday 17th November 2019

Candidates must have a first class or upper second class honours BSc Honours/MSc in Chemistry, Biochemistry, Biophysics, or a similar subject. Some laboratory experience is required, along with scientific curiosity and a keen interest in research.



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