7KAA

NMR solution structures of tirasemtiv drug bound to a fast skeletal troponin C-troponin I complex

Summary for 7KAA

• Entry DOI: 10.2210/pdb7kaa/pdb
• NMR Information: BMRB: 30801
• Descriptor: Troponin C, skeletal muscle,Troponin I, fast skeletal muscle chimera, CALCIUM ION, 6-ethynyl-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyrazin-2-ol (3 entities in total)
• Functional Keywords: activator, contractile protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 17366.98

Authors

Mercier, P.,Li, M.X.,Hartman, J.J.,Sykes, B.D. (deposition date: 2020-09-30, release date: 2021-03-24, Last modification date: 2024-05-15)

Primary citation

Li, M.X.,Mercier, P.,Hartman, J.J.,Sykes, B.D.
Structural Basis of Tirasemtiv Activation of Fast Skeletal Muscle.
J.Med.Chem., 64:3026-3034, 2021

PubMed Abstract: 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, , amplifies the response of muscle to neuromuscular input. 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 bound to a fast skeletal troponin C-troponin I chimera. The structure reveals that 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.

PubMed: 33703886
DOI: 10.1021/acs.jmedchem.0c01412

Experimental method

SOLUTION NMR