Crystal structure of the ligand binding suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor

Binding of inositol 1,4,5-trisphosphate (IP3) to the amino-terminal region Of IP3 receptor promotes Ca2+ release from the endoplasmic reticulum. Within the amino terminus, the first 220 residues directly preceding the IP3 binding core domain play a key role in IP3 binding suppression and regulatory protein interaction. Here we present a crystal structure of the suppressor domain of the mouse type 1 IP3 receptor at 1.8 Angstrom. Displaying a shape akin to a hammer, the suppressor region contains a Head subdomain forming the beta-trefoil fold and an Arm subdomain possessing a helix-turn-helix structure. The conserved region on the Head subdomain appeared to interact with the IP3 binding core domain and is in close proximity to the previously proposed binding sites of Homer, RACK1, calmodulin, and CaBP1. The present study sheds light onto the mechanism underlying the receptor's sensitivity to the ligand and its communication with cellular signaling proteins.