Revisiting channel allostery: a coherent mechanism in IP₃ and ryanodine receptors

The inositol 1,4,5-trisphosphate (IP₃) receptor is an IP₃-gated calcium ion (Ca²⁺) channel that mediates intracellular IP₃-Ca²⁺ signaling. A fundamental question--how IP₃ gates the Ca²⁺ channel within the IP₃ receptor--remains unanswered. A new crystal structure of the N-terminal region of the IP₃ receptor reveals allosteric changes by ligand binding and its similarity to the corresponding region of ryanodine receptor. Docking of the crystal structures in the electron microscopy map and an IP₃ receptor-ryanodine receptor chimera consistently supported a coherent gating mechanism in these receptors. An intriguing feature was the long distance between the IP₃-binding sites and the Ca²⁺ channel, suggesting that long-range allosteric coupling occurs between these regions upon gating of the channel. These results help integrate previous knowledge on the IP₃ and ryanodine receptors and also provide a new framework for understanding the gating mechanism.