Mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin

John A. Rohde, Osha Roopnarine, David D. Thomas, Joseph M. Muretta

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)E7486-E7494
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number32
DOIs
StatePublished - Aug 7 2018

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