Structural basis for activation and gating of IP₃ receptors

A pivotal component of the calcium (Ca²⁺) signaling toolbox in cells is the inositol 1,4,5-triphosphate (IP₃) receptor (IP₃R), which mediates Ca²⁺ release from the endoplasmic reticulum (ER), controlling cytoplasmic and organellar Ca²⁺ concentrations. IP₃Rs are co-activated by IP₃ and Ca²⁺, inhibited by Ca²⁺ at high concentrations, and potentiated by ATP. However, the underlying molecular mechanisms are unclear. Here we report cryo-electron microscopy (cryo-EM) structures of human type-3 IP₃R obtained from a single dataset in multiple gating conformations: IP₃-ATP bound pre-active states with closed channels, IP₃-ATP-Ca²⁺ bound active state with an open channel, and IP₃-ATP-Ca²⁺ bound inactive state with a closed channel. The structures demonstrate how IP₃-induced conformational changes prime the receptor for activation by Ca²⁺, how Ca²⁺ binding leads to channel opening, and how ATP modulates the activity, providing insights into the long-sought questions regarding the molecular mechanism underpinning receptor activation and gating.