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Publication Abstract from PubMed

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.

Conformational motions and ligand-binding underlying gating and regulation in IP(3)R channel.,Fan G, Baker MR, Terry LE, Arige V, Chen M, Seryshev AB, Baker ML, Ludtke SJ, Yule DI, Serysheva II Nat Commun. 2022 Nov 14;13(1):6942. doi: 10.1038/s41467-022-34574-1. PMID:36376291^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.