d-Myoinositol 1,4,5-trisphophate 3-kinases (IP₃-3Ks) play important roles in metazoan cellular signaling. It has been demonstrated that mice without a functional version of IP₃-3K isoform B are deficient in peripheral T-cells, indicating that IP₃-3KB is essential to the developing immune system. The recent apo IP₃-3KA structure exhibited a helix at the catalytic domain N-terminus exhibited a helix at the N-terminus of the catalytic domain, with a tryptophan indole moiety mimicking the binding mode of the substrate ATP purine ring, suggesting a mechanism of autoinhibition. Here we present the structure of the complete catalytic domain of IP₃-3KB, including the CaM binding domain in complex with Mg²⁺ and ATP. The crystal structure reveals a homodimeric arrangement of IP₃-3KB catalytic domains, mediated via an intermolecular antiparallel β-sheet formed from part of the CaM binding region. Residues from the putative autoinhibitory helix are rearranged into a loop configuration, with extensive interactions with the bound ATP. Mutagenesis of residues from this region reveals that substitution of the putative autoinhibitory tryptophan generates a hyperactive enzyme which retains Ca²⁺/CaM sensitivity. The IP₃-3KB structure suggests a mechanism of enzyme activation, and raises the possibility that an interaction between IP₃-3KB molecules may occur as part of the catalytic or regulatory cycle.