Chloé Van Leene
Glucocorticoids bind the glucocorticoid receptor (GR) to control immune responses and drive metabolic pathways. Synthetic variants of glucocorticoids have been developed to battle inflammation and cancer. However, their chronic use leads to severe side effects and therapy resistance. GR, which is also a transcription factor, is an intriguing protein as the structure of this multi-domain protein dynamically responds to interactions with ligands, other proteins (e.g. coregulators), and glucocorticoid response elements in the DNA. As a result, several research programs focus on understanding the molecular mechanisms steering the receptor’s many different structures and on developing new, often non-steroidal ligands that drive GR into the most optimal structure in terms of beneficial effects for patients under (synthetic) glucocorticoid treatment.
My promoters’ research groups have jointly discovered that the structural plasticity of GR can be revealed by proteomics in an in vitro setup. My aim is to develop a highly controllable technology in which a promiscuous protease is activated in living cells to then introduce cuts in surface-accessible regions of proteins in their natural environment, this to study protein structures and changes thereof. By a comparative analysis using various ligands of GR, I expect to reveal, using a quantitative mass spectrometry read-out, how GR's structure is being controlled in its natural environment. I will thus develop a powerful assay that allows classifying ligands for GR at the early step of target engagement. This way ligands with a similar behavior, esp. those with a better therapeutic benefit, will be identified in a faster and more reliable manner.