Project Leader: Sebastian Glatt, PhD
Partner: Captor Therapeutics Inc. (Wroclaw)
Main goal is to develop a strategy for the structural studies of ubiquitin ligases from the kulin family and their complexes using crystallography and cryo-EM.
Cooperation between academia and industry is at the core of this project, conducted as part of the Doctoral School of Exact and Natural Sciences and the Malopolska Center of Biotechnology (MCB), both part of the Jagiellonian University (UJ). With this in mind, a doctorate studies opportunity arises for students to be trained in science with a socioeconomic approach, learning and conducting experiments at MCB and with entrepreneurs that hire the selected students on the basis of qualifications.
Among the qualified participants admitted in the fourth edition of the doctoral school were Priyanka Dahate and Kamil Przytulski from the Max Planck Research Group, under the supervision of dr Sebastian Glatt in MCB.
Targeted -protein degradation (TPD) is the highly-specific pharmacological removal of proteins responsible for promoting pathological conditions in humans. Its great therapeutic potential based on the targeting of proteins without enzymatic function or active sites, and that are not usually available to conventional low-molecular-weight inhibitors. In addition, unlike traditional drugs, TPD is less likely to cause drug resistance and require much lower therapeutic doses.
To date, several strategies for TPD have been developed, though the common denominator is the use of low-molecular compounds termed „degraders” to induce the formation of pathological protein with ubiquitin E3 ligases . As a result of the chemically induced rapprochement, the pathological proteins can then be labeled with polyubiquitin chains and directed to degradation in the proteasome.
Solving the geometry and structure of the complexes that comprise E3 ligases, degraders and pathological proteins is a technological problem in the forefront of this project’s goals. This is fundamental to understand why the formation of the complex alone does not guarantee protein degradation in the model cell lines. This inactivity has been hypothesized to come from poor compound absorption in the cells or unproductive architecture of the degradation complex, but its true raison d’etre has been elusive for quite a while. Thus we aim at identifying in in vitro systems the recruitment of E3 ligase to pathological proteins for the modification of chemical compounds that will overcome this, a process that is laborious and fraught with risk. Determining the structure of the protein-E3 ligase will have a significant impact on the optimization strategies, including changing the chemical topology of the degrader. This has meant the recruitment of a very committed group of people to deal with this in a determined and efficient way.
Project financed from the state budget (co-financing and total investment cost)