Structural basis for rosuvastatin-induced activation of skeletal muscle ryanodine receptor 1.

Statin therapies, used to lower high blood cholesterol, have been proposed to cause skeletal muscle side effects including myalgia and rhabdomyolysis. The ryanodine receptor 1 (RyR1)/Ca²⁺ release channel in skeletal muscle has recently been identified as an off-target binder of statins. Here, we report the cryo-electron microscopy structure of RyR1 in complex with rosuvastatin. Rosuvastatin occupies a single binding site in the pore region of RyR1 stabilizing the open conformation. In the closed conformation, the rosuvastatin binding site is occupied by the RyR1 auxiliary transmembrane helices (TMx1-2). Structural comparison indicates steric overlap of rosuvastatin with simvastatin (at Sim-1) but not with atorvastatin on RyR1, while all these statins may interfere with the conformational stability of the TMx1-2 helices. In contrast to simvastatin and atorvastatin, rosuvastatin does not exhibit multiple binding sites on RyR1 while similarly promoting RyR1 activation, indicating its potential as a preferable lead structure for developing statins that minimizes adverse side effects on RyR1.