Conformational landscape and clustering of human type 2 IP3 receptor in lipid nanodiscs

Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) are tetrameric ER Ca2+ channels that shape intracellular Ca2+ signaling in response to IP3, regulating many physiological processes. The structural basis for subtype-specific regulation of three subtypes (IP3R-1-3) remains incompletely understood, due to the lack of IP3R-2 structures. Here, we determined cryo-electron microscopy (cryo-EM) structures of human IP3R-2 in distinct conformations with and without IP3, Ca2+, and ATP. These structures define the conformational ensembles adopted by IP3R-2 and delineate ligand-binding interactions. Comparison with rat IP3R-1 and human IP3R-3 highlights shared architectural features and isoform-specific differences that underlie subtype-specific functional properties. We also resolved structures of IP3R-2 clusters, providing insight into mechanisms of ligand-dependent clustering. Together, these findings establish a structural framework for human IP3R-2, linking ligand recognition to conformational transitions and interchannel interfaces, and illuminate how subtype-specific features and clustering may shape cellular Ca2+ signaling.