A drug and ATP binding site in type 1 ryanodine receptor

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 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-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.

Keywords: Rycals; calcium channels; calmodulin; calstabin; cryoEM; electrophysiology; ion channels; muscular dystrophy; ryanodine receptor; sarcoplasmic reticulum.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Binding Sites
  • Calcium* / metabolism
  • Muscle, Skeletal / metabolism
  • Ryanodine Receptor Calcium Release Channel* / genetics
  • Ryanodine Receptor Calcium Release Channel* / metabolism
  • Sarcoplasmic Reticulum / metabolism


  • Ryanodine Receptor Calcium Release Channel
  • Adenosine Triphosphate
  • Calcium