Cryo-EM structure of the folded-back state of human -cardiac myosin

To save energy and precisely regulate cardiac contractility, cardiac muscle myosin heads are sequestered in an 'off' state that can be converted to an 'on' state when exertion is increased. The 'off' state is equated with a folded-back structure known as the interacting-heads motif (IHM), which is a regulatory feature of all class-2 muscle and non-muscle myosins. We report here the human beta-cardiac myosin IHM structure determined by cryo-electron microscopy to 3.6 angstrom resolution, providing details of all the interfaces stabilizing the 'off' state. The structure shows that these interfaces are hot spots of hypertrophic cardiomyopathy mutations that are thought to cause hypercontractility by destabilizing the 'off' state. Importantly, the cardiac and smooth muscle myosin IHM structures dramatically differ, providing structural evidence for the divergent physiological regulation of these muscle types. The cardiac IHM structure will facilitate development of clinically useful new molecules that modulate IHM stability. The authors report the high-resolution structure of human beta-cardiac myosin in its sequestered state. The results provide insights into the cardiac regulation and represent a tool to investigate the development of inherited cardiomyopathies.