Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers
Abstract
Cardiac muscle contraction is powered by ATP hydrolysis during cycles of interaction between myosin-containing thick filaments and actin-containing thin filaments. This generates force in the cardiac muscle necessary for pumping blood through the body. Mutations in myosin alter this force generation leading to hypercontractility and hypertrophic cardiomyopathy (HCM). An energy-conserving, super relaxed state (SRX) of myosin, which has a very low ATPase activity, has previously been described in muscle fibers. Destabilization of the SRX has been proposed to be a chief cause of HCM. This work sheds light on the biochemical and molecular nature of SRX and demonstrates the mechanism of action of mavacamten, a cardiac inhibitor in phase 2 clinical trials. Mavacamten exerts its effects primarily by stabilizing the SRX of β-cardiac myosin.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- August 2018
- DOI:
- 10.1073/pnas.1809540115
- Bibcode:
- 2018PNAS..115E8143A