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Title page for ETD etd-07282017-083534


Type of Document Dissertation
Author Alvin, Joseph William
URN etd-07282017-083534
Title Structure-Function Study of Large Clostridial Toxins and their Glucosyltransferase Domains
Degree PhD
Department Chemical and Physical Biology
Advisory Committee
Advisor Name Title
Al Beth Committee Chair
Nick Reiter Committee Member
Tim Cover Committee Member
Keywords
  • Clostridium difficile
  • glucosyltransferase
  • large clostridial toxin
Date of Defense 2017-06-22
Availability restrictsix
Abstract
C. difficile is the leading cause of hospital-acquired diarrhea and pseudomembranous colitis worldwide. The major virulence factors in CDI (TcdA and TcdB) are members of the Large Clostridial Toxin (LCT) family. Due to the growing global healthcare burden of C. difficile, it remains the most-studied of the LCT-producing Clostridia. In an effort to further our understanding, I sought to study the structural characteristics of the TcdA/B-GTD using a combination of sequence comparison, structural modeling, crosslinking, and crystallography with substrates and inhibitors. Despite substitutions in the synthetic compound, the active site and sugar selection residues remained unchanged in both proteins compared to the native substrate. Overall, my work contributes to the study of LCT-GTDs by identifying promising methods for crosslinking and providing new structures of TcdA and TcdB-GTD using a non-hydrolyzable analog and the small molecule apigenin. In determining the five new structures of TcdA and TcdB-GTD we observed disparate conformations of the active site tryptophan.
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