4.8 Article

Structural basis for activation and gating of IP3 receptors

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NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41467-022-29073-2

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  1. U.S. National Institute of Health (NIH) [S10RR031634]
  2. NIH [R01GM141251]
  3. Vanderbilt University, Vanderbilt Diabetes and Research Training Center [NIH P30DK020593]
  4. Molecular Biophysics Training Program [NIH T32GM008320]

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This study presents cryo-EM structures of human type-3 IP3 receptors, revealing the molecular mechanism of receptor activation. The structures demonstrate how IP3-induced conformational changes prime the receptor for activation by Ca2+, and how ATP modulates the activity.
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. IP(3)Rs 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. IP3 receptors are intracellular calcium channels involved in numerous signaling pathways. Here, the authors present the cryo-EM structures of type-3 IP3 receptors in multiple gating conformations, including the active state revealing the molecular mechanism of the receptor activation.

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