Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 433, Issue 23, Pages -Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2021.167295
Keywords
Super-Relaxed State (SRX); Interacting Heads Motif (IHM); Small Angle-X-ray Scattering (SAXS); mavacamten; blebbistatin
Categories
Funding
- DOE Office of Science [DE-AC0206CH11357]
- National Institute of General Medical Sciences of the National Institutes of Health [P41 GM103622]
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This study examined the effects of two myosin ATPase inhibitors on myosin structure, finding that they can induce different relaxation states. Mavacamten and para-nitroblebbistatin may stabilize myosin in distinct structural states, which could lead to different functional energy-saving states.
In addition to a conventional relaxed state, a fraction of myosins in the cardiac muscle exists in a low-energy consuming super-relaxed (SRX) state, which is kept as a reserve pool that may be engaged under sustained increased cardiac demand. The conventional relaxed and the super-relaxed states are widely assumed to correspond to a structure where myosin heads are in an open configuration, free to interact with actin, and a closed configuration, inhibiting binding to actin, respectively. Disruption of the myosin SRX population is an emerging model in different heart diseases, such as hypertrophic cardiomyopathy, which results in excessive muscle contraction, and stabilizing them using myosin inhibitors is budding as an attractive therapeutic strategy. Here we examined the structure-function relationships of two myosin ATPase inhibitors, mavacamten and para-nitroblebbistatin, and found that binding of mavacamten at a site different than para-nitroblebbistatin populates myosin into the SRX state. Para-nitroblebbistatin, binding to a distal pocket to the myosin lever arm near the nucleotide-binding site, does not affect the usual myosin SRX state but instead appears to render myosin into a new, perhaps much more inhibited, `ultra-relaxed' state. X-ray scattering-based rigid body modeling shows that both mavacamten and para-nitroblebbistatin induce novel conformations in human beta-cardiac heavy meromyosin that diverge significantly from the hypothetical open and closed states, and furthermore, mavacamten treatment causes greater compaction than para-nitroblebbistatin. Taken together, we conclude that mavacamten and para-nitroblebbistatin stabilize myosin in different structural states, and such states may give rise to different functional energy-sparing states. (C) 2021 The Author(s). Published by Elsevier Ltd.
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