Grant: Travel Awards - Institute Community Support

Tuberculosis (TB) is the leading cause of mortality from a single infectious agent worldwide. In Canada, TB is a health crisis among Indigenous peoples with incidence levels reaching a staggering 294 times higher than non-Indigenous Canadians. The lack of an effective vaccine and the continued spread of multidrug-resistant Mycobacterium tuberculosis (MDR)-Mtb threaten to undermine the progress made against TB. The Mtb proteasome is a complex machinery responsible for degrading damaged or non-functional proteins. It comprises a 20S core particle that performs the actual degradation and regulatory particles that act as 'gatekeepers,' facilitating the transport of proteins into the core for degradation. Access to the core's degradation chamber, housing 14 catalytic sites, is restricted and controlled by these regulatory particles. My research seeks to understand the allosteric - or long-range - mechanisms that modulate the function of the Mtb proteasome. Utilizing a blend of structural biology techniques and biochemical assays, we aim to unravel how conformational changes and allosteric regulation influence the proteasome's function. Our goal is to identify specific allosteric sites that could be targeted by small molecules to inhibit the proteasome's activity selectively, thereby offering a novel avenue for drug development against MDR-Mtb.