Structure of IPR channel: high-resolution insights from cryo-EM.

Inositol 1,4,5-trisphosphate receptors (IPRs) are ubiquitously expressed intracellular Ca channels and the major mediators of cellular Ca signals generated by the release of Ca ions from intracellular stores in response to a variety of extracellular stimuli. Despite established physiological significance and proven involvements of IPR channels in many human diseases, detailed structural basis for signal detection by these ion channels and their gating remain obscure. Recently, single particle electron cryomicroscopy (cryo-EM) has yielded a long-awaited near-atomic resolution structure of the entire full-length type 1 IPR. This structure provided exciting mechanistic insights into the molecular assembly of IPR, revealing the pronounced structural conservation of Ca release channels and raising many fundamental and controversial questions on their activation and gating. Here we summarize the major technological advances that propelled our cryo-EM analysis of IPR to near-atomic resolution and discuss what the future holds for structural biology of Ca release channels.