Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) are ubiquitous intracellular Ca2+ channels. IP3 binding to the IP3-binding core (IBC) near the N terminus initiates conformational changes that lead to opening of a pore. The mechanisms underlying this process are unresolved. We synthesized 2-O-modified IP3 analogs that are partial agonists of IP3R. These are similar to IP3 in their interactions with the IBC, but they are less effective than IP3 in rearranging the relationship between the IBC and the N-terminal suppressor domain (SD), and they open the channel at slower rates. IP3R with a mutation in the SD occupying a position similar to the 2-O substituent of the partial agonists has a reduced open probability that is similar for full and partial agonists. Bulky or charged substituents from either the ligand or the SD therefore block obligatory coupling of the IBC and the SD. Analysis of. G for ligand binding shows that IP3 is recognized by the IBC and conformational changes then propagate entirely via the SD to the pore.