骨骼肌
肌钙蛋白C
肌钙蛋白
肌钙蛋白I
化学
钙
肌钙蛋白复合物
生物物理学
肌钙蛋白T
生物化学
内科学
医学
生物
有机化学
心肌梗塞
作者
Monica X. Li,Pascal Mercier,James J. Hartman,Brian D. Sykes
标识
DOI:10.1021/acs.jmedchem.0c01412
摘要
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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