National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01GM072804
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01GM080139
米国
National Institutes of Health/National Institute of Dental and Craniofacial Research (NIH/NIDCR)
DE019245
米国
Welch Foundation
AU-2014-20190330
米国
Welch Foundation
AU-2014-20220331
米国
American Heart Association
18CDA34110086
米国
Cancer Prevention and Research Institute of Texas (CPRIT)
RP190602
米国
引用
ジャーナル: Nat Commun / 年: 2022 タイトル: Conformational motions and ligand-binding underlying gating and regulation in IPR channel. 著者: 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 / 要旨: Inositol-1,4,5-trisphosphate receptors (IPRs) are activated by IP and Ca and their gating is regulated by various intracellular messengers that finely tune the channel activity. Here, using single ...Inositol-1,4,5-trisphosphate receptors (IPRs) are activated by IP and Ca 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 IPR1 channel in two ligand-bound states. These structures provide unprecedented details governing binding of IP, Ca 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 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 IPR channels. This work represents a stepping-stone to developing mechanistic understanding of conformational pathways underlying ligand-binding, activation and regulation of the channel.