Towards a better diagnostic for active tuberculosis: NMR solution structure and mutational engineering of protein Rv1980c from M. tuberculosis

M. tuberculosis protein Rv1980c and its homologs form a highly conserved family of secreted proteins found within the pathogenic Mycobacteria genus. The founding member of this family is expressed only when M. tuberculosis cells are actively dividing. By virtue of this relatively unique expression profile, Rv1980c is currently under phase III clinical trials to evaluate its efficacy in a transdermal patch test for detection of active tuberculosis (TB) infection (PTAT). Previous studies have suggested that a single T‐cell reactive epitope within Rv1980c is responsible for the “delayed‐type hypersensitivity” reaction associated with exposure to Rv1980c in TB‐positive individuals, and that this epitope is comprised of a 15‐residue core region (CE15) between Gly173 and Glu186 of the mature polypeptide. We are using NMR structural and dynamic studies of Rv1980c in conjunction with animal infection models to develop a more potent version of the PTAT. Here we report the high resolution NMR solution structure of Rv1980c, which adopts a previously unclassified fold, and which reveals that the CE15 region of Rv1980c adopts a highly ordered structure. Current studies toward enhancement of the Rv1980c‐based PTAT by incorporating multiple copies of CE15 within dynamic regions of Rv1980c will also be presented.