My lecture will start out with very brief remarks on the history of protein crystallography and continue with our studies since 1970 on proteolytic enzymes and their control. Proteolytic enzymes catalyse a very simple chemical reaction, the hydrolytic cleavage of a peptide bond. Nevertheless they constitute a most diverse and numerous lineage of proteins. The reason lies in their role as components of many regulatory physiological cascades in all organisms. To serve this purpose and to avoid unwanted destructive action, proteolytic activity must be strictly controlled. Control is based on different mechanisms some of which I will discuss and illustrate with examples of systems and structures determined in my laboratory: a) by specific inhibition with natural and synthetic inhibitors, b) by enzymatic specificity, c) by activation from inactive precursors accompanied or not by allosteric changes,d) by co-localization of enzyme and substrate, e) by cofactor binding accompanied or not by allosteric changes, f) by controlled access to the active site and g) by substrate-induced allosteric changes of the active site associated with oligomerization.The regulatory principles unveiled by structural studies offer new opportunities of intervention for therapeutic purposes as illustrated with the essential intracellular protease, the proteasome.
I then will let you share my experience with the foundation and development of two biotech companies with different business models, but both based on basic academic research in structural biology: Proteros (www.proteros.com) offers enabling technology services for Pharma- and Crop science companies imbedding all steps of the workflow molecular and structural biology can provide and commands and uses its platform for the generation of leads from identified targets to in vivo Proof of Concept (PoC). Suppremol (www.suppremol.com) specializes in the development of novel immune-regulatory therapeutics for the treatment of autoimmune diseases on the basis of a recombinant, soluble, non-glycosylated version of the human Fcy receptor IIB and of receptor binding antibodies. Suppremol was recently acquired by Baxter International Inc. (NYSE:BAX) offering an ideal setting for its therapeutic projects.