Fig. 4: The modulation of RyR1 by Ca²⁺, ATP, Caffeine, and S0. Two opposite protomers are displayed with domains in a cartoon.

a RyR1 in resting state without Ca²⁺ and the channel is closed. b In the presence of Ca²⁺, but S0 is decoupled to pVSD, RyR1 is in a primed state with a closed gate. c In the presence of Ca²⁺ and S0 is coupled to pVSD, RyR1 have two conformations (solid box), which are primed (gate is closed) and activated states (gate is open). d In the presence of Ca²⁺, ATP, and S0 is coupled to pVSD, RyR1 is in full open state. e In the presence of Ca²⁺ and ATP but S0 is decoupled to pVSD, RyR1 is in the primed state with a closed gate. f In the presence of Ca²⁺, ATP, and exogenous regulator (e.g., caffeine), RyR1 have two conformations (dashed box), which are primed (gate is closed) and open states (gate is open)^24,36. g Schematic diagram of RyR1 channel gating mechanism. Ca²⁺/ATP/Caf regulates the channel through ɑ4/U motif-VSC-pVSD-S4/S5 linker-gate path (path I) and U motif/CTD-S6c path (path II), as indicated by the gray arrows. When S0 is coupled to pVSD, Ca²⁺/ATP regulates the channel through ɑ4/U motif-VSC-pVSD-S0-S4/S5 linker-gate path (path I) and path II. S0 enhances the coupling of pVSD with the S4/S5 linker, greatly facilitating the dilation of S6. h Color codes for the various domains and compounds. The positions of each domain within the full-length RyR1 are also marked. The dotted rectangular outline for S0 indicates that the density for S0 was not observed in the corresponding cryo-EM structures.