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Mechanism and Inhibition of Bacterial Primase; and, Evaluation of the UNL Chemistry TA Mentoring Program
There are two distinct parts of this dissertation – the mechanism and inhibition of bacterial primase, and evaluation of the UNL Chemistry TA mentoring program. In chapter 1, the NMR structure of Staphylococcus aureus primase C-Terminal Domain (CTD) was determined in collaboration with Dr. Powers’ lab. It consisted of two sub-domains connected by a flexible linker. Next, several small molecules were discovered to bind weakly in the groove between the sub-domains of the S. aureus CTD closed conformation (non-helicase binding conformation). Our hypothesis was that these small molecules could be antibiotic leads if their binding affinity could be strengthened. The small molecule would stabilize the protein in its compact state which would interfere with the helicase binding. This is important because primase CTD must be in its open conformation to bind to its cognate helicase at the replication fork. In chapter 2, the S. aureus primase CTD sequence and structure were compared to other medically relevant bacterial primases. Although the primase CTD sequences are very poorly conserved, they have highly conserved protein folds, which were then used to align the sequences by hand. Multi-sequence analysis tools determine that there was a strong phylogenetic split between Gram-positive and Gram-negative primase sequences. This suggested that primase would be a good narrow-range antibiotic target. Furthermore, three critical residues at the interface with the helicase were identified, and there was significant sequence conservation at the groove between the sub-domains. In chapter 3, we described the TA mentor program that was initiated in Fall 2014 with the purpose of improving lab TA success and leadership. We determined that the program had multiple positive impacts. It met its goals to guide the TAs throughout the semester, and to increase grading consistency between lab sections. From the students’ perspective, their experience and performance were both enhanced as shown by the reduction of the DFW rate.
Periago, Jessica, "Mechanism and Inhibition of Bacterial Primase; and, Evaluation of the UNL Chemistry TA Mentoring Program" (2022). ETD collection for University of Nebraska - Lincoln. AAI29167194.