The structural basis of myosin activation and regulation in health and disease

Myosin is an astounding biological machine capable of generating mechanical force from ATP hydrolysis and its interaction with filamentous actin, critical to many facets of life. It makes up a superfamily of proteins, with 12 unique classes in the human genome alone, each responsible for a diverse range of functions from muscle contraction to cellular transport. Due to its ubiquitous nature and critical role, it is also involved in many diseases. One such area is heart disease, contributing to significant social and economic burden. Heart disease such as hypertrophic cardiomyopathy and systolic heart failure have a significant impact on public health, whilst current therapies are limited to symptomatic relief or invasive procedures. This has led to the development of direct myosin small molecule modulators in an attempt to better tackle disease progression. However, the understanding of how these new modulators function is unclear making application in disease challenging. This lack of understanding stems from the complexity of the disease pathology as well as missing information on key aspects of myosin force generation. Thus, in this thesis I aim to progress our understanding of myosin force generation by revealing the critical mechanism of myosin actin activation, resolving decades of conjecture on how myosin generates movement. Subsequently by applying this new understanding I reveal the mechanism of three myosin modulators mavacamten, omecamtiv mecarbil and danicamtiv used to treat cardiac disease. The improved understanding of these modulators will allow for better clinical application and assist in the development of next generation modulators improving patient therapy.