Myosin in autoinhibited off state(s), stabilized by mavacamten, can be recruited via inotropic effectors.

ABSTRACT: Mavacamten is a novel, FDA-approved, small molecule therapeutic designed to regulate cardiac function by selectively but reversibly inhibiting the enzymatic activity of myosin. It shifts myosin towards ordered off states close to the thick filament backbone. It remains unresolved whether mavacamten permanently sequesters these myosin heads in the off state(s) or whether these heads can be recruited in response to physiological stimuli when required to boost cardiac output. We show that cardiac myosins stabilized in these off state(s) by mavacamten are recruitable by Ca²⁺, increased heart rate, stretch, and β-adrenergic (β-AR) stimulation, all known physiological inotropic effectors. At the molecular level, we show that, in presence of mavacamten, Ca^2+</

SUBMITTER: Ma W 

PROVIDER: S-EPMC10120679 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature