RGD Reference Report - Conformational motions and ligand-binding underlying gating and regulation in IP3R channel. - Rat Genome Database

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

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 
Citation: Fan G, etal., Nat Commun. 2022 Nov 14;13(1):6942. doi: 10.1038/s41467-022-34574-1.
RGD ID: 405650379
Pubmed: PMID:36376291   (View Abstract at PubMed)
PMCID: PMC9663519   (View Article at PubMed Central)
DOI: DOI:10.1038/s41467-022-34574-1   (Journal Full-text)

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.




Biological Process

  
Object Symbol
Species
Term
Qualifier
Evidence
With
Notes
Source
Original Reference(s)
Itpr1Ratprotein homotetramerization involved_inIDA PMID:36376291UniProt 

Molecular Function

  
Object Symbol
Species
Term
Qualifier
Evidence
With
Notes
Source
Original Reference(s)
Itpr1RatATP binding enablesIDA PMID:36376291UniProt 
Itpr1Ratinositol 1,4,5 trisphosphate binding enablesIDA PMID:36376291UniProt 


Genes (Rattus norvegicus)
Itpr1  (inositol 1,4,5-trisphosphate receptor, type 1)