Structural basis for activation and gating of IP3 receptors

Calcium (Ca 2+ ) is a universal and versatile cellular messenger used to regulate numerous cellular processes in response to external or internal stimuli. A pivotal component of the Ca 2+ signaling toolbox in cells is the inositol 1,4,5-triphosphate (IP 3 ) receptors (IP 3 Rs), which mediate Ca 2+ release from the endoplasmic reticulum (ER), controlling cytoplasmic and organellar Ca 2+ concentrations 1-3 . IP 3 Rs are activated by IP 3 and Ca 2+ , inhibited by Ca 2+ at high concentrations, and potentiated by ATP 1-3 . However, the underlying molecular mechanisms are unclear due to the lack of structures in the active conformation. Here we report cryo-electron microscopy (cryo-EM) structures of human type-3 IP 3 R 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 of the receptor activation and gating.