Cryo-EM structure of shutdown human non-muscle myosin 2A

Determining the high-resolution structure of the widely expressed non-muscle myosin 2A (NM2A), in its dephosphorylated shutdown state, is important in understanding its regulation and disease roles. In shutdown molecules, the coiled-coil tail wraps around the myosin heads preventing them from forming filaments and binding to actin. We have solved the shutdown structure of NM2A to a global resolution of 3 angstroms in the heads region, and 6.3 angstroms for the whole molecule. This reveals specific ionic interactions that explain why the path of the coiled coil and the shutdown mechanism for NM2A differs from that of β-cardiac myosin and provides key insight into how specific mutations likely destabilize the shutdown state, leading to disease.