ENZYMATIC INVESTIGATION AND STRUCTURE-BASED DRUG DESIGN OF TERMINAL URIDYLYLTRAN

Stanford University, Stanford CA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Terminal uridylyl transferases (TUTases) are a class of RNA-editing enzymes capable of uridine nucleotide insertion into mRNA transcripts in a template-independent manner. This process is quite extensive in the mitochondria of trypanosomes and these enzymes therefore serve as drug targets for the development of new trypanocides. Eight out of twelve mitochondrial transcripts must be edited in this fashion in order to encode functional proteins, some of which comprising as much as 50% U-insertions in their fully-edited form. This project involves solving the structure of one such enzyme, TbTUT4, with a novel small-molecule inhibitor bound which has been shown to inhibit nucleotide incorporation activity and cell growth of T. brucei. The structure of this complex will lead to further optimization of this drug by improving its binding affinity. The project will also involve solving the crystal structure of a related enzyme, TbMEAT1, whose crystals are very weakly diffracting, even after attempts at optimization, and require synchrotron radiation for reasonable diffraction.