Inositol 1,4,5-trisphosphate receptors (IP₃R) are large (~1.2MDa) tetrameric intracellular Ca²⁺ channels predominantly located in the endoplasmic reticulum. They are responsible for initiating and propagating the Ca²⁺ signals evoked by the diverse extracellular stimuli that initiate the phosphatidylinositol signalling cascade. Overall each monomeric subunit comprises an inositol 1,4,5-trisphosphate (IP₃) binding core at its N-terminus, a transmembrane region comprising six transmembrane segments towards its C-terminus and an intervening regulatory domain. It is still not clear how these different domains are structurally arranged and how they interact during channel activation. We have used electron microscopy and single particle analysis to calculate the structure of the type I IP₃R in the absence of IP₃ and Ca²⁺, which are its native regulators (1). By relating the organisation of the structural domains in the resulting 3D map to secondary structure predictions and biochemical data we have developed a structural model in which the amino acid sequence was mapped onto the domains formed by the densities of the 3D reconstruction. Similar methods have now been used to investigate the effect of IP₃ binding upon the structure of IP₃R. A direct comparison between the maps obtained for the unliganded and IP₃ bound IP₃R reveals substantial rearrangements of the structural domains. Furthermore, the location of the binding site of IP₃ within IP₃R has been inferred by calculating a 3D map of the IP₃R bound to a novel higly electron dense undecagold derivative of IP₃ coupled via a reactive amine attached to the 2-position of IP₃. Although the new 3D maps of the IP₃R allowed a direct observation of the extent of the conformational reorganisation associated with channel activation, at the present resolution levels no direct information can be gained from these maps on the molecular mechanisms underlying channel gating and conductance properties. However, information on these mechanisms can be obtained using high resolution structural information already available for related families of channel proteins. This involves a careful aminoacid sequence alignment between members of the different protein families and the constructions of homology models, followed by a validating analysis of the model by its consistence with available biochemical data. Here the structural basis by which Ca²⁺ conductivity of IP₃R is regulated has been investigated using aminoacid sequence analysis to produce models for the transmembrane region of IP₃R in its closed and open states, using the x-ray crystallographic structures of two bacterial K⁺ channels KirBac (2) and MtHK (3) as templates, respectively. From these models we proposed a common mechanism for channel opening for tetrametic K+ channels and the IP₃R. Furthermore, it was possible to infer onto the molecular basis of cation selectivity between the highly selective K⁺ channels and the Ca²⁺ channels, IP₃R and ryanodine receptor.