Gating machinery of InsP3R channels revealed by electron cryomicroscopy

Inositol-1,4,5-trisphosphate receptors (InsP(3)Rs) are ubiquitous ion channels responsible for cytosolic Ca2+ signalling and essential for a broad array of cellular processes ranging from contraction to secretion, and from proliferation to cell death. Despite decades of research on InsP(3)Rs, a mechanistic understanding of their structure-function relationship is lacking. Here we present the first, to our knowledge, near-atomic (4.7 angstrom) resolution electron cryomicroscopy structure of the tetrameric mammalian type 1 InsP(3)R channel in its apo-state. At this resolution, we are able to trace unambiguously similar to 85% of the protein backbone, allowing us to identify the structural elements involved in gating and modulation of this 1.3-megadalton channel. Although the central Ca2+-conduction pathway is similar to other ion channels, including the closely related ryanodine receptor, the cytosolic carboxy termini are uniquely arranged in a left-handed a-helical bundle, directly interacting with the amino-terminal domains of adjacent subunits. This configuration suggests a molecular mechanism for allosteric regulation of channel gating by intracellular signals.