Grant: Doctoral Research Award: Canada Graduate Scholarships

Whenever we have a muscle contraction, whether that occurs in our legs when we go for a walk or every time our heart beats, our body sends signals to proteins in our muscles to initiate this process. Ryanodine receptors (RyRs) are proteins within our muscles that receive this signal and trigger a muscle contraction. Hundreds of inheritable disease-causing mutations have been identified in RyRs with the vast majority leading to the overactivity of these proteins. Resulting diseases include malignant hyperthermia, a disorder that causes the body to go into shock when exposed to various anesthetics prior to a medical procedure, and sarcopenia, progressive muscle degeneration particularly prevalent in elderly populations. Currently, dantrolene is the only clinically available drug to treat RyR specific disorders. However, dantrolene is therapeutically limited due to its use resulting in many undesirable side effects. As a result, there is a need to accelerate the design of better drugs against RyRs. To better understand how RyRs are activated, cryogenic electron-microscopy (cryo-EM) will be used to image known endogenous activator ATP, and its fragments, bound directly to RyRs. These images are a way to visualize snapshots of protein movements along with the exact binding poses for each ATP fragment. Such visualization provides a basis for targeted drug design, allowing us to design molecules that fit specifically within this pocket to outcompete the activating effects of ATP. Combined with established drug design approaches, these techniques will accelerate the development of new therapeutics. Multiple chemotherapeutic drugs that have toxic effects on the heart have been shown to have off target effects on RyRs, some of which are believed to bind to the same pocket that ATP binds. Visualizing how these drugs bind to RyRs will provide a platform to modify these compounds to not fit within their binding pocket, preventing the negative cardiotoxic effects of these drugs.