Structural basis for the regulation of inositol trisphosphate receptors by Ca 2+ and IP 3 .

Inositol trisphosphate receptors (IP3 Rs) are ubiquitous Ca2+ -permeable channels that mediate release of Ca2+ from the endoplasmic reticulum, thereby regulating numerous processes including cell division, cell death, differentiation and fertilization. IP3 Rs are jointly activated by inositol trisphosphate (IP3 ) and their permeant ion, Ca2+ . At high concentrations, however, Ca2+ inhibits activity, ensuring precise spatiotemporal control over intracellular Ca2+ . Despite extensive characterization of IP3 R, the mechanisms through which these molecules control channel gating have remained elusive. Here, we present structures of full-length human type 3 IP3 Rs in ligand-bound and ligand-free states. Multiple IP3 -bound structures demonstrate that the large cytoplasmic domain provides a platform for propagation of long-range conformational changes to the ion-conduction gate. Structures in the presence of Ca2+ reveal two Ca2+ -binding sites that induce the disruption of numerous interactions between subunits, thereby inhibiting IP3 R. These structures thus provide a mechanistic basis for beginning to understand the regulation of IP3 R.