Cryo-EM reveals ligand induced allostery underlying InsP3R channel gating

• Published in: Cell research 2018-12, Vol.28 (12), p.1158-1170
• Main Authors: Fan, Guizhen, Baker, Mariah R., Wang, Zhao, Seryshev, Alexander B., Ludtke, Steven J., Baker, Matthew L., Serysheva, Irina I.
• Format: Article
• Language: English
• Subjects: 101/28; 631/535/1258/1259; 631/80/86/1999; Adenophostin A; Binding; Biomedical and Life Sciences; Calcium (intracellular); Calcium channels; Calcium ions; Cell Biology; Cerebellum; Channel gating; Conduction; Domains; Hydrophobicity; Inositol 1,4,5-trisphosphate receptors; Ion channels; Life Sciences; Ligands; Receptors; Switches
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/s41422-018-0108-5

Inositol-1,4,5-trisphosphate receptors (InsP 3 Rs) are cation channels that mobilize Ca 2+ from intracellular stores in response to a wide range of cellular stimuli. The paradigm of InsP 3 R activation is the coupled interplay between binding of InsP 3 and Ca 2+ that switches the ion conduction pathway between closed and open states to enable the passage of Ca 2+ 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 InsP 3 R1 from rat cerebellum determined to 4.1 Å resolution in the presence of activating concentrations of Ca 2+ and adenophostin A (AdA), a structural mimetic of InsP 3 and the most potent known agonist of the channel. Comparison with the 3.9 Å-resolution structure of InsP 3 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 InsP 3 R channel.