Mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 32; pp. E7486 - E7494
• Main Authors: Rohde, John A., Roopnarine, Osha, Thomas, David D., Muretta, Joseph M.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07.08.2018
• Series: PNAS Plus
• Subjects: Actin; Actins - metabolism; Adenosine diphosphate; Adenosine Diphosphate - metabolism; Adenosine triphosphatase; Adenosine Triphosphate - metabolism; Allosteric properties; Allosteric Regulation - drug effects; ATP; Benzylamines - pharmacology; Benzylamines - therapeutic use; Biochemistry; Biological Sciences; Cardiac Myosins - chemistry; Cardiac Myosins - metabolism; Cardiomyopathy; Cardiomyopathy, Hypertrophic, Familial - drug therapy; Cardiomyopathy, Hypertrophic, Familial - etiology; Fragmentation; Heart; Humans; Kinetics; Molecular biology; Myosin; Myosin Subfragments - chemistry; Myosin Subfragments - metabolism; PNAS Plus; Protein Stability - drug effects; Proteins; Rotation; Uracil - analogs & derivatives; Uracil - pharmacology; Uracil - therapeutic use; cardiac myosin; mavacamten; hypertrophic cardiomyopathy; superrelaxed state; allosteric inhibitor
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1720342115

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.