Conformational motions and ligand-binding underlying gating and regulation in IP3R channel

Inositol-1,4,5-trisphosphate receptors (IP 3 Rs) are activated by IP 3 and Ca 2+ and their gating is regulated by various intracellular messengers that finely tune the channel activity. Here, using single particle cryo-EM analysis we determined 3D structures of the nanodisc-reconstituted IP 3 R1 cha...

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Bibliographic Details
Published in:Nature communications 2022-11, Vol.13 (1), p.6942-6942, Article 6942
Main Authors: Fan, Guizhen, Baker, Mariah R., Terry, Lara E., Arige, Vikas, Chen, Muyuan, Seryshev, Alexander B., Baker, Matthew L., Ludtke, Steven J., Yule, David I., Serysheva, Irina I.
Format: Article
Language:English
Subjects:
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ATP
BASIC BIOLOGICAL SCIENCES
Binding
Calcium
Calcium channels
Calcium ions
Channel gating
Channel opening
Cryoelectron microscopy
Humanities and Social Sciences
Inositol 1,4,5-trisphosphate receptors
Inositols
Ion transport
Ligand-gated ion channels
Ligands
multidisciplinary
Science
Science (multidisciplinary)
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Summary:Inositol-1,4,5-trisphosphate receptors (IP 3 Rs) are activated by IP 3 and Ca 2+ and their gating is regulated by various intracellular messengers that finely tune the channel activity. Here, using single particle cryo-EM analysis we determined 3D structures of the nanodisc-reconstituted IP 3 R1 channel in two ligand-bound states. These structures provide unprecedented details governing binding of IP 3 , Ca 2+ and ATP, revealing conformational changes that couple ligand-binding to channel opening. Using a deep-learning approach and 3D variability analysis we extracted molecular motions of the key protein domains from cryo-EM density data. We find that IP 3 binding relies upon intrinsic flexibility of the ARM2 domain in the tetrameric channel. Our results highlight a key role of dynamic side chains in regulating gating behavior of IP 3 R channels. This work represents a stepping-stone to developing mechanistic understanding of conformational pathways underlying ligand-binding, activation and regulation of the channel. Here authors report cryo-EM structures of IP 3 R1 which provide atomic details of IP 3 , Ca 2+ and ATP binding. Molecular motions of key domains and sidechains were found to regulate ligand binding and gating, which are validated by functional assays.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-022-34574-1