| Autor: |
Li, Monica X., Mercier, Pascal, Hartman, James J., Sykes, Brian D. |
| Zdroj: |
Journal of Medicinal Chemistry; March 2021, Vol. 64 Issue: 6 p3026-3034, 9p |
| Abstrakt: |
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. Tirasemtivbinds 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 tirasemtivbound to a fast skeletal troponin C–troponin I chimera. The structure reveals that tirasemtivbinds 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. |
| Databáze: |
Supplemental Index |
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