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Revealing Reactivity in Cancer-Associated Heme Proteins: Novel Time-Resolved Structural Approaches

Principal Supervisor: Dr Hanna Kwon

Secondary Supervisor(s): Dr Philip Ash

University of Registration: University of Leicester

BBSRC Research Themes: Understanding the Rules of Life (Structural Biology)

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Deadline: 4 January, 2024


Project Outline

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme involved in the degradation of tryptophan to kynurenine. Cancer cells upregulate IDO1 to escape normal immune responses and, in many cases, a high expression of IDO1 is connected to poor prognosis. Understanding the precise mechanisms by which IDO1 modulates these processes is of paramount importance for therapeutic development and a deeper comprehension of immune homeostasis.

This project aims to investigate the catalytic mechanism and structural dynamics of IDO1 using cutting-edge structural and spectroscopic techniques, and computational analysis. Spectroscopy offers a powerful means to probe the intricate molecular events occurring during IDO1 catalysis in real-time. A combination of X-ray and time-resolved vibrational spectroscopic methods will be used to probe mechanistic details of IDO1. These methods will provide critical data on catalytic timescales that will feed directly into cutting-edge time-resolved structural studies.

The outcomes promise to extend our understanding of this crucial enzyme and its implications in health and disease, with potential far-reaching impacts in immunology and drug discovery.

A PhD student will gain a broad range of interdisciplinary skills in structural biology, chemical biology and biophysics in order to address an important question in cancer biology.

Techniques

  • Molecular Biology (cloning & mutagenesis)
  • Protein expression and purification (bacterial and mammalian)
  • Enzyme kinetics
  • Protein crystallisation
  • Structure determination
  • X-ray Spectroscopy
  • Time-resolved spectroscopy (infrared, Raman)
  • Synchrotron science
  • Chemical synthesis