Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA.
Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA; Department of Anesthesiology, Columbia University, New York, NY, USA.
Structure. 2022 Jul 7;30(7):1025-1034.e4. doi: 10.1016/j.str.2022.04.010. Epub 2022 May 16.
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 Ca 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-Å resolution before local refinement, revealing a binding site in the RY1&2 domain (3.10 Å local resolution), where the Rycal ARM210 binds cooperatively with ATP and stabilizes the closed state of RyR1.
肌质网上的 Ryanodine 受体（RyR）/钙释放通道是骨骼肌和心肌兴奋-收缩偶联所必需的。遗传突变和应激诱导的翻译后修饰导致 SR Ca 渗漏，从而导致骨骼肌病、心力衰竭和运动引起的猝死。一类被称为 Rycals 的治疗药物可防止 RyR 介导的渗漏，在动物模型中有效预防疾病进展和恢复功能，并且正在进行针对肌肉和心脏疾病患者的临床试验。通过低温电子显微镜，我们在局部细化之前呈现了一个分辨率为 2.45 Å 的 RyR1 模型，揭示了 RY1&2 结构域中的一个结合位点（局部分辨率为 3.10 Å），Rycal ARM210 在该位点与 ATP 协同结合并稳定 RyR1 的关闭状态。
