Mavacamten inhibits myosin activity by stabilizing the myosin interacting-heads motif and stalling motor force generation
2026-04-29
Most sudden cardiac deaths in young people arise from hypertrophic cardiomyopathy, a genetic heart muscle disease. Treatment has until recently been limited to symptomatic relief or invasive procedures. Small-molecule modulators of cardiac myosin are promising therapeutic options to target disease progression. Mavacamten, the first Food and Drug Administration–approved example, has an unclear mechanism. To address this, we solved cryo–electron microscopy (cryo-EM) structures of beta-cardiac heavy meromyosin in three adenosine 5′-diphosphate and inorganic phosphate (ADP.P i )–bound states, the primed motor domain with and without mavacamten and the autoinhibited interacting-heads motif (IHM) with mavacamten, to 2.9, 3.4, and 3.7 Å global resolution, respectively. Together with quantitative cross-linking mass spectrometry analysis, these structures reveal how mavacamten inhibits myosin. Mavacamten stabilizes ADP.P i binding, stalling the motor domain in a primed state, reducing motor dynamics required for actin-binding cleft closure, and slowing progression through the force generation cycle. These effects propagate within the two-headed molecule, stabilizing the IHM through increased motor-motor contacts. While this promotes diastolic relaxation, it also reduces systolic contractile output.