Cardiac myosin conformations and interactions with actin filaments in relaxed and activated muscle. (a) Representation of a cardiac sarcomere composed of interdigitated myosin filaments (purple) connected at the M-line and actin filaments anchored at the Z-disk. (b) In relaxed muscle, myosin motors that emanate from the myosin filament backbone exist either in the enzymatically auto-inhibited, SRX state, which can be stabilized by adopting the IHM and precludes thin filament binding, or in the DRX state that is capable actin filament attachment and force generation upon cardiac activation. (c) Once activated, only DRX (i.e., active heads) myosin is recruited to generate force. (d) Proposed mechanism by which the DCM-associated E525K β-cardiac myosin mutation (yellow starburst) stabilizes the IHM/SRX state, reducing the available pool of myosin motors for force generation, leading to cardiac hypo-contractility. Since most humans are heterozygote for cardiac myosin mutations, only one myosin head is depicted with the mutation.