Conformational footprints of agonism: differences of inositol 1,4,5-trisphosphate (IP3) and adenophostin A (AdA) on IP3 receptor’s N-terminal dynamics

Abstract Inositol 1,4,5-trisphosphate receptor (IP3R) represents a major family of intracellular Ca2+-release channels. Distal to its pore-forming region lies its cytoplasmic N-terminus (NT) that harbours the agonist-binding pocket. Although inositol 1,4,5-trisphosphate (IP3) is the endogenous agonist, the fungal metabolite adenophostin A (AdA) is known to function as a ‘super-agonist’, displaying roughly 10-fold higher affinity on binding. Using all-atom molecular dynamics simulations of rat IP3R1 NT in apo, IP3-bound and AdA-bound states, we here show that both agonists alter NT’s flexibility, yet principal component analysis reveals that AdA drives the domain into broader and distinct conformational substates that are visited by neither the apo nor the IP3-bound form. AdA occupies a more spacious, hydrophobic pocket, engaging a wider spectrum of transient polar and non-polar contacts and favouring an entropy-dominated binding mode despite fewer enduring hydrogen bonds. Dynamic cross-correlation analysis further demonstrates that AdA enhances long-range correlated motions across the NT domain. Taken together, the data indicate that AdA’s superior potency arises from its unique capacity to remodel NT dynamics more profoundly than IP3, thereby pre-configuring or priming IP3R for activation gating. These findings refine current models of ligand efficacy and offer a framework for the rational design of next-generation IP3R modulators.