Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand

In a variety of cells, the Ca2+ signalling process is mediated by the endoplasmic-reticulum-membrane-associated Ca2+ release channel, inositol 1,4,5-trisphosphate (InsP(3)) receptor (InsP(3)R)(1). Being ubiquitous and present in organisms ranging from humans to Caenorhabditis elegans, InsP(3)R has a vital role in the control of cellular and physiological processes as diverse as cell division, cell proliferation, apoptosis, fertilization, development, (b)ehaviour, memory and learning(2). Mouse type I InsP(3)R (InsP(3)R1), found in high abundance in cerebellar Purkinje cells, is a polypeptide with three major functionally distinct regions: the amino-terminal InsP(3)-binding region, the central modulatory region and the carboxy-terminal channel region (2). Here we present a 2.2-Angstrom crystal structure of the InsP(3)-binding core of mouse InsP(3)R1 in complex with InsP(3). The asymmetric, boomerang-like structure consists of an N-terminal beta-trefoil domain and a C-terminal alpha-helical domain containing an 'armadillo repeat'-like fold. The cleft formed by the two domains exposes a cluster of arginine and lysine residues that coordinate the three phosphoryl groups of InsP(3). Putative Ca2+-binding sites are identified in two separate locations within the InsP(3)-binding core.