Fig. 1: Cryo-EM reconstructions of human RyR2-S2808D: Rycal ARM210 stabilizes the closed state while calstabin-2 depletion induces the primed state.

a Overlapped models of closed RyR2 (PDB:7UA5, gray) and open RyR2 (PDB:7UA9, yellow). The arrows show that the cytoplasmic shell of the channel shifts downward-outward when going from the closed to the open state. To facilitate visualization only the front protomer is shown in colors, while the other three protomers are shown as gray transparent volumes. The sarcoplasmic reticulum membranes are shown as black discs. b Overlapped models of closed RyR2 (PDB:7UA5, gray) and subprimed RyR2-S2808D (PDB:8UQ2, magenta). The arrows show that the cytoplasmic shell of the channel shifts downward-outward when going from the closed to the subprimed state. c RMSD normalized projection of WT RyR2 and RyR2-S2808D channels with different treatments. Values close to 0 or 1 indicate the conformation of the cytoplasmic shell is more similar to the closed WT RyR2 (PDB:7UA5), or the open WT RyR2 (PDB:7UA9), respectively. Negative values indicate the conformation of the cytoplasmic shell is more upward-inward than the closed state. d Overlapped models of subprimed RyR2-S2808D (PDB:8UQ2, magenta) and closed RyR2-S2808D + ARM210 (PDB:8UQ3, cyan). The arrows show that the cytoplasmic shell of the channel in the presence of ARM210 shifts upward-inward reversing the primed state back towards the closed state. e Same as (b) but with primed RyR2-S2808D + rapamycin (PDB:8UQ5, green). f, g cryo-EM maps focused on casltabin-2 (cyan) binding site of RyR2-S2808D (f) and RyR2-S2808D + rapamycin (g).