IP₃-mediated gating mechanism of the IP₃ receptor revealed by mutagenesis and X-ray crystallography

The inositol 1,4,5-trisphosphate (IP₃) receptor (IP₃R) is an IP₃-gated ion channel that releases calcium ions (Ca²⁺) from the endoplasmic reticulum. The IP₃-binding sites in the large cytosolic domain are distant from the Ca²⁺ conducting pore, and the allosteric mechanism of how IP₃ opens the Ca²⁺ channel remains elusive. Here, we identify a long-range gating mechanism uncovered by channel mutagenesis and X-ray crystallography of the large cytosolic domain of mouse type 1 IP₃R in the absence and presence of IP₃. Analyses of two distinct space group crystals uncovered an IP₃- dependent global translocation of the curvature α-helical domain interfacing with the cytosolic and channel domains. Mutagenesis of the IP₃R channel revealed an essential role of a leaflet structure in the α-helical domain. These results suggest that the curvature α-helical domain relays IP₃-controlled global conformational dynamics to the channel through the leaflet, conferring long-range allosteric coupling from IP₃ binding to the Ca²⁺ channel.