Work

Cryo-EM reveals ligand induced allostery underlying InsP3R channel gating

Year: 2018

Type: article

Abstract: 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.

Source: Cell Research

DOI: 10.1038/s41422-018-0108-5