The Central domain of RyR1 is the transducer for long-range allosteric gating of channel opening

Cell Res. 2016 Sep;26(9):995-1006. doi: 10.1038/cr.2016.89. Epub 2016 Jul 29.


The ryanodine receptors (RyRs) are intracellular calcium channels responsible for rapid release of Ca(2+) from the sarcoplasmic/endoplasmic reticulum (SR/ER) to the cytoplasm, which is essential for the excitation-contraction (E-C) coupling of cardiac and skeletal muscles. The near-atomic resolution structure of closed RyR1 revealed the molecular details of this colossal channel, while the long-range allosteric gating mechanism awaits elucidation. Here, we report the cryo-EM structures of rabbit RyR1 in three closed conformations at about 4 Å resolution and an open state at 5.7 Å. Comparison of the closed RyR1 structures shows a breathing motion of the cytoplasmic platform, while the channel domain and its contiguous Central domain remain nearly unchanged. Comparison of the open and closed structures shows a dilation of the S6 tetrahelical bundle at the cytoplasmic gate that leads to channel opening. During the pore opening, the cytoplasmic "O-ring" motif of the channel domain and the U-motif of the Central domain exhibit coupled motion, while the Central domain undergoes domain-wise displacement. These structural analyses provide important insight into the E-C coupling in skeletal muscles and identify the Central domain as the transducer that couples the conformational changes of the cytoplasmic platform to the gating of the central pore.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Animals
  • Cryoelectron Microscopy
  • Cytoplasm / metabolism
  • Excitation Contraction Coupling
  • Ion Channel Gating*
  • Models, Molecular
  • Protein Domains
  • Rabbits
  • Ryanodine Receptor Calcium Release Channel / chemistry*
  • Ryanodine Receptor Calcium Release Channel / metabolism*
  • Ryanodine Receptor Calcium Release Channel / ultrastructure
  • Structure-Activity Relationship


  • Ryanodine Receptor Calcium Release Channel