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Grupa badawcza prof. Tad Holak

Kierownik grupy

prof. dr Tad Holak

Research group

Chemical Biology and Drug Discovery; Faculty of Chemistry, Jagiellonian University, Kraków, Poland

Research

The research interests of the group lie in the area of chemical biology. We use small-molecule probes to study biologic processes underlying growth and proliferation of human cancer cells. Specifically, our research has uncovered several small-molecule probes of oncogenic protein-protein interactions (PPIs). An example is provided with the small-molecule inhibitors of the Mdm2/x-p53 interaction. The tumor suppressor p53 protein, "the guardian of the genome," is crucial for protecting the organism against cancer. The Mdm2/x proteins inhibit protective activity of p53.

Techniques

The techniques used to study the PPIs are: nuclear magnetic resonance and X-ray crystallography, combined with procedures of molecular biology and cell-based screening.

Representative publications

  1. Krajewski, M., Ozdowy, P., D'Silva, L., Rothweiler, U. and Holak T.A. (2005). NMR indicates that the small molecule RITA does not block the p53-MDM2 binding in vitro. Nature Medicine 11, 1135-1136.
  2. Popowicz, G.M., Schleicher, M., Noegel, A.A. and Holak, T.A. (2006). Filamins: promiscuous organizers of the cytoskeleton. Trends Bioch. Sci. 31, 411-419.
  3. Riedl, J., Crevenna, A.H., Kessenbrock, K., Yu, J.H., Neukirchen, D., Bista, M., Bradke, F., Jenne, D., Holak, T.A., Werb, Z., Sixt, M. and Wedlich-Soldner R. (2008). Lifeact: a versatile marker to visualize F-actin. Nature Methods 5, 605-607.
  4. Bista, M., Kowalska, K., Janczyk, W., Dömling, A. and Holak, T.A. (2009). Robust NMR screening for lead compounds using tryptophan-containing proteins. J. Amer. Chem. Soc. 131, 7500-7501.
  5. Sitar, T., Gallinger, J., Ducka, A. M., Ikonen, T.P., Wohlhoefler, M., Schmoller, K.M., Bausch, A.R., Joel, P., Trybus, K.M., Noegel, A.A., Schleicher, M., Huber, R. and Holak, T.A. (2011). Molecular architecture of the Spire-actin nucleus and its implication for actin filament assembly. Proc. Nat. Acad. Sci. USA, 108, 19575- 19580.   
  6. Popowicz, G.M., Doemling, A. and Holak, T.A. (2011). The structure-based design of Mdm2/­Mdmx-p53 inhibitors gets serious. Angew. Chem. Int. Ed. 50, 2680-2688.
  7. Mishra, S.K., Ammon, T., Popowicz, G.M., Krajewski, M., Nagel, R.J., Ares M. Jr., Holak, T.A. and Jentsch, S. (2011). Role of the ubiquitin-like protein Hub1 in splice site usage and alternative splicing. Nature, 474, 173-178.
  8. Baek, S., Kutchukian, P.S., Verdine G.L, Huber, R., Holak, T.A. Lee, K.W. Popowicz, G.M. (2012). Structure of the stapled p53 peptide bound to Mdm2. J. Amer. Chem. Soc. 134, 103-106.
  9. Bista, M., Wolf, S., Khoury, K., Kowalska, K., Huang, Y., Wrona, E., Arciniego, M., Popowicz, G.M., Holak, T.A. and Domling A. (2013). Transient protein states in designing inhibitors of the MDM2-p53 interaction. Structure 21, 2143-2151.
  10. Doemling, A. and Holak, T. A. (2014). Programmed death-1: therapeutic success after more than 100 years of cancer immunotherapy. Angew. Chem. Int. Ed. 53, 2286-2288.