IP ₃ -mediated gating mechanism of the IP ₃ receptor revealed by mutagenesis and X-ray crystallography

Abstract

Significance Cells use chemical signals for intracellular communication in our bodies. Inositol 1,4,5-trisphosphate (IP 3 ) is a chemical signal that binds to the IP 3 receptor (IP 3 R) to release calcium ions from the endoplasmic reticulum. The distance from ligand-binding sites to the channel within IP 3 R is the longest among known ligand-gated ion channels, and the fundamental question of how IP 3 -binding physically opens the channel remains unanswered. Here, we solved IP 3 -bound and unbound structures of large cytosolic domains of the IP 3 R by X-ray crystallography and clarified the IP 3 -dependent gating mechanism through a unique leaflet structure. These findings reveal a principle of long-range allosteric coupling in ligand-gated ion channels and provide drug targets for IP 3 R-regulated events, including autophagy, apoptosis, cancers, and brain disorders.