Cryo-EM reveals ligand induced allostery underlying InsP3R channel gating. Issue 12 (December 2018)

• Record Type: Journal Article
• Authors: Fan, Guizhen; Baker, Mariah; Wang, Zhao; Seryshev, Alexander; Ludtke, Steven; Baker, Matthew; Serysheva, Irina
• Is Part Of: Cell research. Volume 28:Issue 12(2018)
• Page Start: 1158
• Page End: 1170
• Publication Date: 2018-12
• Subjects: Cells -- Periodicals; Cytology -- Periodicals; Molecular biology -- Periodicals; 571.6
• DOI: 10.1038/s41422-018-0108-5
• Languages: English
• ISSNs: 1001-0602

Abstract

Abstract Inositol-1, 4, 5-trisphosphate receptors (InsP3 Rs) are cation channels that mobilize Ca2+ from intracellular stores in response to a wide range of cellular stimuli. The paradigm of InsP3 R activation is the coupled interplay between binding of InsP3 and Ca2+ that switches the ion conduction pathway between closed and open states to enable the passage of Ca2+ through the channel. However, the molecular mechanism of how the receptor senses and decodes ligand-binding signals into gating motion remains unknown. Here, we present the electron cryo-microscopy structure of InsP3 R1 from rat cerebellum determined to 4.1 Å resolution in the presence of activating concentrations of Ca2+ and adenophostin A (AdA), a structural mimetic of InsP3 and the most potent known agonist of the channel. Comparison with the 3.9 Å-resolution structure of InsP3 R1 in the Apo-state, also reported herein, reveals the binding arrangement of AdA in the tetrameric channel assembly and striking ligand-induced conformational rearrangements within cytoplasmic domains coupled to the dilation of a hydrophobic constriction at the gate. Together, our results provide critical insights into the mechanistic principles by which ligand-binding allosterically gates InsP3 R channel.