Abstract
Granzyme B (GRZB) is the most abundant protease present in the granules of cytotoxic immune cells present and plays a key role in targeted cancer cell killing by the immune system. In tumors, the amount of GRZB that is secreted by activated immune cells, is inversely correlated with the degree of immunosuppression. Therefore, GRZB is quantified in tumor biopsies of patients treated with immune checkpoint inhibitors. Moreover, significant research effort is going to the discovery of Positron Emission Tomography (PET)-probes that allow minimally-invasive imaging of GRZB. This approach is also relevant for CAR T and CAR NK cell therapy, where the amount of released GRZB correlates with therapy response. Within a Marie Curie Doctoral Network 'OncoProTools' we are conducting research on novel GRZB activity-based probes. The recruited postdoc will contribute to this effort in the following ways:
(i) Production and purification of GrzB via an in-house recombinant expression system; (ii) Structural biology: elucidation of the structure of 3 [GRZB-probe] co-complexes and determination of the probe binding modes via macromolecular X-ray crystallography; (iii) Kinetic characterization of the probes: determination of binding parameters via jump-dilution assays, progress curve analysis, eventually combined with grating-coupled interferometry; (iv) Synthesis of optimized probes: Preparation of further optimized GRZB probes.
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