Two Classes of Myosin Inhibitors, Para-nitroblebbistatin and Mavacamten, Stabilize beta-Cardiac Myosin in Different Structural and Functional States.

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Gollapudi SK, Ma W, Chakravarthy S, Combs AC, Sa N, Langer S, Irving TC, Nag S

Two Classes of Myosin Inhibitors, Para-nitroblebbistatin and Mavacamten, Stabilize beta-Cardiac Myosin in Different Structural and Functional States.

J Mol Biol. 2021 Nov 19;433(23):167295. doi: 10.1016/j.jmb.2021.167295. Epub 2021 Oct 8.

PubMed ID
34627791 [ View in PubMed
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Abstract

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.

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