Structural dynamics underlying gating and regulation in IP ₃ R 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 channel in two ligand-bound states. These structures provide unprecedented details governing binding of IP ₃ , Ca ²⁺ and ATP in IP ₃ R1, revealing conformational changes that couple ligand-binding to channel opening. Using a GMM based deep learning approach and 3D variability analysis, we extracted dynamic properties of the key protein domains. From this, we find that IP ₃ binding relies upon intrinsic flexibility of the cytoplasmic ARM2 domain. Our results highlight a key role of dynamic side chains surrounding the ion conduction path in regulating gating behavior of IP ₃ R channels. Altogether, this work defines a structural platform for mechanistic understanding of the molecular dynamics underlying ligand-binding, activation and regulation of the IP ₃ R activity.