Key result
Mavacamten cuts cardiac myosin ATPase cycling ~76% by stabilizing an autoinhibited state.
Mavacamten acts by stabilizing an autoinhibited state specific to two-headed cardiac myosin, providing a molecular basis for its efficacy in hypertrophic cardiomyopathy.
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Supports myosin inhibition in HCM models; leaves open translation from in vitro data to clinical use.
We used transient biochemical and structural kinetics to elucidate the molecular mechanism of mavacamten, an allosteric cardiac myosin inhibitor and a prospective treatment for hypertrophic cardiomyopathy. We find that mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin not found in the single-headed S1 myosin motor fragment. We determined this by measuring cardiac myosin actin-activated and actin-independent ATPase and single-ATP turnover kinetics. A two-headed myosin fragment exhibits distinct autoinhibited ATP turnover kinetics compared with a single-headed fragment. Mavacamten enhanced this autoinhibition. It also enhanced autoinhibition of ADP release. Furthermore, actin changes the structure of the autoinhibited state by forcing myosin lever-arm rotation. Mavacamten slows this rotation in two-headed myosin but does not prevent it. We conclude that cardiac myosin is regulated in solution by an interaction between its two heads and propose that mavacamten stabilizes this state.
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Rohde et al. (2018) studied Hypertrophic cardiomyopathy. Mavacamten vs. Untreated control / absence of mavacamten was evaluated on Steady-state actin-activated ATPase cycling rate (kcat) in two-headed cardiac heavy meromyosin (HMM) (p=≤0.001). Mavacamten stabilized an autoinhibited state of two-headed cardiac heavy meromyosin in vitro, reducing steady-state actin-activated ATPase cycling (kcat) from 2.02 to 0.48 s-1 (p≤0.001).
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