Activation of IP3 receptors by synthetic bisphosphate ligandsw

Ca release by D-myo-inositol 1,4,5-trisphosphate receptors (IP3Rs) is widely considered to require the vicinal 4,5-bisphosphate motif of IP3, with P-5 and P-4 engaging the a and b domains of the binding site; using synthesis and mutagenesis we show that the adenine of synthetic glyconucleotides, through an interaction with Arg504, can replace the interaction of either P-1 or P-5 with the a-domain producing, respectively, the most potent bisphosphate agonist yet synthesised and the first agonist of IP3R without a vicinal bisphosphate motif; this will stimulate new approaches to IP3R ligand design.