Abstract
Inositol trisphosphate receptors (IP(3)Rs) are ubiquitous Ca(2+)-permeable channels that mediate release of Ca(2+) from the endoplasmic reticulum, thereby regulating numerous processes including cell division, cell death, differentiation and fertilization. IP(3)Rs are jointly activated by inositol trisphosphate (IP(3)) and their permeant ion, Ca(2+). At high concentrations, however, Ca(2+) inhibits activity, ensuring precise spatiotemporal control over intracellular Ca(2+). Despite extensive characterization of IP(3)R, the mechanisms through which these molecules control channel gating have remained elusive. Here, we present structures of full-length human type 3 IP(3)Rs in ligand-bound and ligand-free states. Multiple IP(3)-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 Ca(2+) reveal two Ca(2+)-binding sites that induce the disruption of numerous interactions between subunits, thereby inhibiting IP(3)R. These structures thus provide a mechanistic basis for beginning to understand the regulation of IP(3)R.