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Structure Determination and Analysis of Terminal Uridylyltransferases by Means of XRay Crystallography for Trypanoside Development Jessica G. Bruystens Mentor: Hartmut Luecke The development of new lead compounds as potential therapeutic agents for the treatment of diseases that are caused by microorganisms comprises a major area of research in the struggle against increased drug resistance. Such is the case for Human African trypanosomiasis (HAT), often called sleeping sickness, which is caused by the protozoan parasite Trypanosoma brucei. During the investigation of Trypanosomes, a new RNA editing system was discovered in their kinetoplast-mitochondria, presenting new possible targets for drug discoveries. We have been structurally analyzing a set of enzymes that are involved in the RNA-editing process or that show sequence homology to the involved enzymes, and have previously determined structures of UTP substrate-bound and apo forms of TbTUT4, a minimal catalytically active RNA uridylyltransferase. To investigate the TbTUT4 reaction of U transfer to the 3’ hydroxyl of mRNA, we have obtained a UTP+TbTUT4+UMP prereaction complex and a postreaction complex of TbTUT4 with UpU. The search for drug candidates has steered our TUTase investigation towards obtaining a crystal structure of TbTUT4 bound with a small molecule inhibitor and to elucidate the structures of TbMEAT-1, TbTUT9, and kPAP, which represent additional potential drug targets. Here we report the progress and challenges in their crystal-based structural investigation.