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 has until recently been limited to symptomatic relief or invasive procedures. However, small molecule modulators of cardiac myosin are promising therapeutic options to target 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 mavacamt

SUBMITTER: McMillan SN 

PROVIDER: S-EPMC11844505 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature