Omecamtiv mecarbil is a selective, small-molecule activator of cardiac myosin 
that is being developed as a potential treatment for heart failure with reduced 
ejection fraction. Here we determine the crystal structure of cardiac myosin in 
the pre-powerstroke state, the most relevant state suggested by kinetic studies, 
both with (2.45 Å) and without (3.10 Å) omecamtiv mecarbil bound. Omecamtiv 
mecarbil does not change the motor mechanism nor does it influence myosin 
structure. Instead, omecamtiv mecarbil binds to an allosteric site that 
stabilizes the lever arm in a primed position resulting in accumulation of 
cardiac myosin in the primed state prior to onset of cardiac contraction, thus 
increasing the number of heads that can bind to the actin filament and undergo a 
powerstroke once the cardiac cycle starts. The mechanism of action of omecamtiv 
mecarbil also provides insights into uncovering how force is generated by 
molecular motors.Omecamtiv mecarbil (OM) is a cardiac myosin activator that is 
currently in clinical trials for heart failure treatment. Here, the authors give 
insights into its mode of action and present the crystal structure of OM bound 
to bovine cardiac myosin, which shows that OM stabilizes the pre-powerstroke 
state of myosin.