PT  - JOURNAL ARTICLE
AU  - Robert L. Anderson
AU  - Darshan V. Trivedi
AU  - Saswata S. Sarkar
AU  - Marcus Henze
AU  - Weikang Ma
AU  - Henry Gong
AU  - Christopher S. Rogers
AU  - Fiona L. Wong
AU  - Makenna M. Morck
AU  - Jonathan G. Seidman
AU  - Kathleen M. Ruppel
AU  - Thomas C. Irving
AU  - Roger Cooke
AU  - Eric M. Green
AU  - James A. Spudich
TI  - Mavacamten stabilizes a folded-back sequestered super-relaxed state of β-cardiac myosin
AID  - 10.1101/266783
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 266783
4099  - http://biorxiv.org/content/early/2018/03/10/266783.short
4100  - http://biorxiv.org/content/early/2018/03/10/266783.full
AB  - Mutations in β-cardiac myosin, the predominant motor protein for human heart contraction, can alter power output and cause cardiomyopathy. However, measurements of the intrinsic force, velocity and ATPase activityof myosin have not provided a consistent mechanism to link mutations to muscle pathology. An alternative modelpositsthat mutations in myosin affect the stability ofa sequestered, super-relaxed state (SRX) of the proteinwith very slow ATP hydrolysis and thereby change the number of myosin heads accessible to actin. Here, using a combination of biochemical and structural approaches, we show that purified myosin enters aSRX thatcorresponds to a folded-back conformation, which in muscle fibersresults insequestration of heads around the thick filament backbone. Mutations that cause HCM destabilize this state, while the small molecule mavacamtenpromotes it. These findings provide a biochemical and structural link between the genetics and physiology ofcardiomyopathywith implications for therapeutic strategies.