Key result
Mavacamten inhibits cardiac myosin by stabilizing ADP.Pi binding, stalling the motor domain in a primed state, and allosterically stabilizing the autoinhibited interacting-heads motif.
Why the study?
Mavacamten is FDA approved for hypertrophic cardiomyopathy, but its molecular mode of action remains unclear, limiting understanding of its functional effects.
Population
Beta-cardiac heavy meromyosin
Comparison
Mavacamten vs absence of mavacamten
Design
CryoEM structural and quantitative crosslinking mass spectrometric analysis
Authors
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May aid next-generation myosin inhibitor design; leaves open correlation with clinical outcomes in HCM.
Mavacamten inhibits cardiac myosin by stabilising the ADP.Pi state and the interacting-heads motif, providing a structural basis for its ability to reduce contractile output in hypertrophic cardiomyopathy.
McMillan et al. (2025) studied Hypertrophic cardiomyopathy. Mavacamten vs. Absence of mavacamten was evaluated on Myosin structural conformation and dynamics. Mavacamten inhibits cardiac myosin by stabilizing ADP.Pi binding, stalling the motor domain in a primed state, and allosterically stabilizing the autoinhibited interacting-heads motif.
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