Cryo-EM studies of activators and inhibitors of KCNQ1 and KCNQ1:KCNE1 channel complexes

Type 1 Long QT syndrome (LQT1) and Short QT syndrome (SQT) result in life-threatening irregular heartbeats that can cause sudden death. LQT1 affects around 1 in 2,500 adults, whereas SQT may impact twice as many individuals, with high prevalence of congenital LQT in a First Nations community in Northern BC. Current treatments are inefficient and therefore, new therapeutic strategies are needed. Abnormalities of the protein, KCNQ1, result in these diseases. Normal KCNQ1 function moves charged ions through heart membranes. We generally know how KCNQ1 functions in health and disease; however, the exact mechanisms are not yet fully understood. We need to study the 3D structural changes that happen to KCNQ1 in the presence of certain compounds to understand how KCNQ1 functions. I will study the 3D structures of such complexes by using cryo-electron microscopy, a technique to study structural biology, and functional characterization. The new knowledge that will be produced will help better understand how such proteins cause disease and lead to new therapeutics for better human health.