Cryo-EM reveals ligand induced allostery underlying InsP 3 R channel gating

Cell Res. 2018 Dec;28(12):1158-1170. doi: 10.1038/s41422-018-0108-5. Epub 2018 Nov 23.

Abstract

Inositol-1,4,5-trisphosphate receptors (InsP3Rs) are cation channels that mobilize Ca2+ from intracellular stores in response to a wide range of cellular stimuli. The paradigm of InsP3R 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 InsP3R1 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 InsP3R1 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 InsP3R channel.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / chemistry
  • Allosteric Regulation
  • Animals
  • Calcium / metabolism*
  • Calcium Signaling*
  • Cerebellum / metabolism*
  • Cryoelectron Microscopy / methods
  • Inositol 1,4,5-Trisphosphate Receptors / agonists
  • Inositol 1,4,5-Trisphosphate Receptors / chemistry*
  • Ion Channel Gating*
  • Ligands
  • Models, Molecular
  • Protein Conformation*
  • Rats

Substances

  • Inositol 1,4,5-Trisphosphate Receptors
  • Ligands
  • adenophostin A
  • Adenosine
  • Calcium