Mavacamten inhibits myosin activity by stabilising the myosin interacting-heads motif and stalling motor force generation

ABSTRACT: Most sudden cardiac deaths in young people arise from hypertrophic cardiomyopathy, a genetic disease of the heart muscle, with many causative mutations found in the molecular motor beta-cardiac myosin that drives contraction. Therapeutic intervention for hypertrophic cardiomyopathy has until recently been limited to symptomatic relief or invasive procedures. However, small molecule modulators of cardiac myosin are promising therapeutic options to better reduce disease progression. Mavacamten is the first example to gain FDA approval but its molecular mode of action remains unclear, limiting our understanding of its functional effects in disease. To better understand this, we solved the cryoEM structures of beta-cardiac heavy meromyosin in three ADP.Pi-bound states, the primed motor domain in the presence and absence of mavacamten, and the sequestered autoinhibited interacting-heads motif (IHM) in complex with mavacamten. Together with in vitro motility and quantitative crosslinking mass spectrometric analysis, these structures reveal how mavacamten inhibits myosin. For this study we adapted the MS1 label-free quantitation presented by Chen and Rappsiliber. Mavacamten stabilises ADP.Pi 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. Within the two-headed myosin molecule, these effects are propagated and lead to stabilisation of the IHM, through increased contacts at the motor-motor interface.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

SUBMITTER: Jaime Pitts  

LAB HEAD: Charlotte Scarf

PROVIDER: PXD059316 | Pride | 2026-03-26

REPOSITORIES: Pride