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Conformational motions and ligand-binding underlying gating and regulation in IP 3 R channel.

Guizhen FanMariah R BakerLara E TerryVikas ArigeMuyuan ChenAlexander B SeryshevMatthew L BakerSteven J LudtkeDavid I YuleIrina I Serysheva
Published in: Nature communications (2022)
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.
Keyphrases
  • molecular dynamics
  • deep learning
  • single molecule
  • molecular dynamics simulations
  • high resolution
  • machine learning
  • dna binding
  • reactive oxygen species
  • high density
  • editorial comment