Structure of RyR1. The sequence map at top identifies domains and segments named following des Georges et al. (2016), in color code that is maintained in the diagrams and labels. The side view has two of the four protomers removed for clarity. The “top” or “en-face” view is as seen from the cytosolic side. The arrows on the en-face view are color-coded, except for three set in black for visibility. In the side view, the double-dash circle (indicated by a curved arrow) encloses the control hub that includes the binding sites of the three canonical agonists: Ca²⁺, ATP, and caffeine. “Sol” stands for the multiple α-solenoid regions, regarded as a relatively inert, convoluted stem from which globular domains hang like fruits. NTD and CTD stand for N- and C-terminal domains, both of which line a central cytosolic-side vestibule. The large SPRY (SP1a kinase and ryanodine receptor) stretch is subdivided into three domains. The tandem Repeats 12 and 34 are also known as P1 and P2. While the diagrams represent RyR1, RyR2 is highly similar. The ellipse at top right in the en-face view marks the domains believed to participate in RyR2–RyR2 “oblique” contacts (cf. Fig. 8), namely, Repeat 12, SPRY1, and the associated protein FKBP12, which in RyR2 could be replaced by RyR12.6. They occupy approximately one third of the edge, leftward of every corner. The diagrams are a gift from Filip Van Petegem (University of British Columbia, Vancouver, Canada).