Travel and Contact  Staff Only  Site Map  Help?     EMBL Hamburg > Courses and Conferences   Invitation   Poster   Speakers   Sponsors   Organisers   Programme   Pictures      16 September      15 September      PDB Exhibition   Marcus Grütter - Markus G. Grütter Department of Biochemistry, University of Zürich Winterthurerstr. 190, CH-8057 Zürich Research in apoptosis and inflammation has established a central role for a specific class of cysteine proteases, the caspases. The crystal structures of several caspases together with biochemical and biophysical studies have greatly enhanced our understanding of these enzymes. One important aspect is the specific inhibition of caspases since they are of high importance in the development of various illnesses, such as neurodegenerative diseases, cancer or inflammatory disorders. We have determined the crystal structures of caspase-3, -8 and -2 with focus on enzyme-inhibitor/substrate interactions (1,2). The structures are used for in silico screening of potential inhibitors from various compound libraries, followed by inhibition assays and structural investigation of the enzyme inhibitor complexes. The aim is to generate selective and potent second generation non-peptidic compounds for analytical and therapeutic applications. Moreover, we have successfully developed a highly specific caspase-2 inhibitor that was selected from a designed ankyrin repeat protein library (3). This caspase inhibitor represents not only the first designed ankyrin repeat protein that inhibits a protease, but more importantly, it is the first example of a specific inhibitor of an initiator caspase. Caspases, as all other proteolytic enzymes, are synthesized as inactive zymogens. Their activation is highly regulated and involves cleavage of the proform. We studied the activation mechanism of the initiator caspase-8 in vitro and found as others, that dimerization and not processing represents the primary event in initiator caspase activation (4). In vivo, this is achieved through the formation of activation platforms such as the apoptosome or the inflammasome, which contain multiple copies of caspases and other regulatory proteins (5). Future research will be dedicated to the structural and functional investigation of such supramolecular complexes. References: Grütter, M.G. (2000) Caspases: key players in programmed cell death. Curr. Opin. Struct. Biol., 10, 649-655. Schweizer, A., Briand, Ch. and Grütter, M.G. (2003) Crystal Structure of Caspase-2, Apical Initiator of the Intrinsic Apoptotic Pathway. J. Biol. Chem. 278, 42441 - 42447. Binz, H.K., Amstutz, P., Kohl, A., Stumpp, M.T., Briand, C., Forrer, P., Grütter, M.G. and Plückthun, A. (2004) Selection and Crystallographic Characterization of High Affinity Binders from Designed Ankyrin Repeat Protein Libraries. Nature Biotech. 22, 575-582. Donepudi, M., Mac Sweeney, A., Briand, Ch. and Grütter, M.G. (2003). Insights into the regulatory mechanism for caspase-8 activation. Mol. Cell, 11, 543-549. Hiller, S., Kohl, A., Fiorito, F., Herrmann, T., Wider, G.,Tschopp, J., Grütter, M.G. and Wüthrich, K. (2003). NMR structure of the apoptosis-and inflammation-related NALP-1 pyrin domain. Structure, 11, 1199-1205.