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Activation of the intracellular Ca 2+  channel ryanodine receptor (RyR) triggers a cytosolic Ca 2+  surge, while elevated cytosolic Ca 2+  inhibits the channel in a negative feedback mechanism. Cryogenic electron microscopy of rabbit RyR1 embedded in nanodiscs under partially inactivating Ca 2+  conditions revealed an open and a closed-inactivated conformation. Ca 2+  binding to the high-affinity site engages the central and C-terminal domains into a block, which pries the S6 four-helix bundle open. Further rotation of this block pushes S6 toward the central axis, closing (inactivating) the channel. Main characteristics of the Ca 2+ -inactivated conformation are downward conformation of the cytoplasmic assembly and tightly knit subunit interface contributed by a fully occupied Ca 2+  activation site, two inter-subunit resolved lipids, and two salt bridges between the EF hand domain and the S2–S3 loop validated by disease-causing mutations. The structural insight illustrates the prior Ca 2+  activation prerequisite for Ca 2+  inactivation and provides for a seamless transition from inactivated to closed conformations.

Ca 2+ inactivation of the mammalian ryanodine receptor type 1 in a lipidic environment revealed by cryo-EM