Authors: Zephan Melville, Haikel Dridi, Qi Yuan, …, Yang Liu, Oliver B. Clarke, Andrew R. Marks
The ryanodine receptor (RyR)/calcium release channel on the sarcoplasmic reticulum (SR) is required for excitation-contraction coupling in skeletal and cardiac muscle. Inherited mutations and stress-induced post-translational modifications result in an SR Ca2+ leak that causes skeletal myopathies, heart failure, and exercise-induced sudden death. A class of therapeutics known as Rycals prevent the RyR-mediated leak, are effective in preventing disease progression and restoring function in animal models, and are in clinical trials for patients with muscle and heart disorders. Using cryogenic-electron microscopy, we present a model of RyR1 with a 2.45-A° resolution before local refinement, revealing a binding site in the RY1&2 domain (3.10 A°local resolution), where the Rycal ARM210 binds cooperatively with ATP and stabilizes the closed state of RyR1.
