Conformational Motions and Ligand-binding Underlying Gating and Regulation in IP3R Channel

Authors

Guizhen Fan
Mariah R Baker
Lara E Terry
Vikas Arige
Muyuan Chen
Alexander B Seryshev
Matthew L Baker
Steven J Ludtke
David I Yule
Irina I Serysheva

Publication Date

11-14-2022

Journal

Nature Communications

Abstract

Inositol-1,4,5-trisphosphate receptors (IP3Rs) are activated by IP3 and Ca2+ 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 IP3R1 channel in two ligand-bound states. These structures provide unprecedented details governing binding of IP3, Ca2+ 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 IP3 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 IP3R channels. This work represents a stepping-stone to developing mechanistic understanding of conformational pathways underlying ligand-binding, activation and regulation of the channel.

Keywords

Inositol 1, 4, 5-Trisphosphate Receptors, Calcium, Ligands, Protein Domains, Inositol 1, 4, 5-Trisphosphate, Calcium Signaling