Key result
Tirasemtiv binds in a hydrophobic pocket between troponin C and troponin I, stabilizing their interface and driving the equilibrium toward the active state.
Why the study?
Muscle weakness in conditions like amyotrophic lateral sclerosis and spinal muscular atrophy stems from diminished neuromuscular output, but the structural mechanism by which the fast skeletal troponin activator tirasemtiv amplifies muscle response was unknown.
The NMR structure reveals the mechanism by which tirasemtiv binds to fast skeletal troponin, stabilizing the troponin C-troponin I interface to sensitize muscle to calcium.
Clarifies tirasemtiv's troponin binding mechanism; leaves open translation to clinical efficacy in humans.
Troponin regulates the calcium-mediated activation of skeletal muscle. Muscle weakness in diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy occurs from diminished neuromuscular output. The first direct fast skeletal troponin activator, tirasemtiv, amplifies the response of muscle to neuromuscular input. Tirasemtiv binds selectively and strongly to fast skeletal troponin, slowing the rate of calcium release and sensitizing muscle to calcium. We report the solution NMR structure of tirasemtiv bound to a fast skeletal troponin C–troponin I chimera. The structure reveals that tirasemtiv binds in a hydrophobic pocket between the regulatory domain of troponin C and the switch region of troponin I, which overlaps with that of Anapoe in the X-ray structure of skeletal troponin. Multiple interactions stabilize the troponin C–troponin I interface, increase the affinity of troponin C for the switch region of fast skeletal troponin I, and drive the equilibrium toward the active state.
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Li et al. (2021) studied this question. Tirasemtiv was evaluated on Solution NMR structure of tirasemtiv bound to a fast skeletal troponin C-troponin I chimera. Tirasemtiv binds in a hydrophobic pocket between troponin C and troponin I, stabilizing their interface and driving the equilibrium toward the active state.
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