Fig. 7. Schematics of ligand-induced structural changes underlying activation of IP₃R1 channel.

a A conformational wave generated upon binding of the activating ligands propagates from the LBDs forming the apical portion of the channel via the ILD/LNK assembly (‘nexus’) towards the channel pore. Depicted are two opposing subunits colored by domains. Domain motions are indicated with arrows. b Conformational changes underlying binding of IP₃, Ca²⁺ and ATP. Intrinsic flexibility of ARM2 domain allows for a reversible ratcheting mechanism where ARM2 switches between ‘extended’ and ‘retracted’ conformations. The extended conformation is restrictive for binding of IP₃ (top left), while ‘extended’ conformation is suitable for capturing IP₃ due to release of structural constraints at interfaces between ARM2 and βTF1' and ARM1' from the neighboring subunit (top right). Allosteric nexus comprising LNK and ILD domains (middle panels) and the channel pore at F2586 (bottom panels) are expanded in the presence of activating ligands. The domains in Ca-IP₃R1 (left column) and CIA-IP₃R1 (right column) structures are viewed along the central 4-fold axis from the cytosol with one subunit outlined in black.