Structural basis for the regulation of inositol trisphosphate receptors by Ca²⁺ and IP₃

Inositol trisphosphate receptors (IP₃Rs) 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. IP₃Rs 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 IP₃R, the mechanisms through which these molecules control channel gating have remained elusive. Here, we present structures of full-length human type 3 IP₃Rs 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 IP₃R. These structures thus provide a mechanistic basis for beginning to understand the regulation of IP₃R.