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

The inositol 1,4,5-trisphosphate (IP) receptor (IPR) is an IP-gated ion channel that releases calcium ions (Ca) from the endoplasmic reticulum. The IP-binding sites in the large cytosolic domain are distant from the Ca conducting pore, and the allosteric mechanism of how IP opens the Ca 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 IPR in the absence and presence of IP Analyses of two distinct space group crystals uncovered an IP-dependent global translocation of the curvature α-helical domain interfacing with the cytosolic and channel domains. Mutagenesis of the IPR channel revealed an essential role of a leaflet structure in the α-helical domain. These results suggest that the curvature α-helical domain relays IP-controlled global conformational dynamics to the channel through the leaflet, conferring long-range allosteric coupling from IP binding to the Ca channel.