Structural basis for activation and gating of IP(3) receptors

A pivotal component of the calcium (Ca(2+)) signaling toolbox in cells is the inositol 1,4,5-triphosphate (IP(3)) receptor (IP(3)R), which mediates Ca(2+) release from the endoplasmic reticulum (ER), controlling cytoplasmic and organellar Ca(2+) concentrations. IP(3)Rs are co-activated by IP(3) and Ca(2+), inhibited by Ca(2+) 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 IP(3)R obtained from a single dataset in multiple gating conformations: IP(3)-ATP bound pre-active states with closed channels, IP(3)-ATP-Ca(2+) bound active state with an open channel, and IP(3)-ATP-Ca(2+) bound inactive state with a closed channel. The structures demonstrate how IP(3)-induced conformational changes prime the receptor for activation by Ca(2+), how Ca(2+) 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.