Crystal structure of human INPP5K with an allosteric inhibitor reveals the structural basis for species specific potency.

Inositol polyphosphate 5-phosphatase K (INPP5K) is a phosphatidylinositol (3,4,5)-trisphosphate phosphatase that increases glucose uptake and regulates myogenesis in the skeletal muscle. To understand the mechanism of its species-specific inhibition, we determined the 1.9-Å resolution crystal structure of human INPP5K in complex with a selective inhibitor, CPD-1 (IC50 = 2.9 µM). The structure reveals that CPD-1 binds to a novel allosteric pocket, inducing a large conformational change in α-helix 3 that alters the active site and prevents substrate binding. This finding explains its unique, noncompetitive inhibitory mechanism. Crucially, while the inhibitor-binding residues are conserved, the key residue governing the allosteric transition is not conserved in mouse and rat INPP5K, which correlates with their insensitivity to CPD-1 (IC50 > 100 µM). Based on these structural insights, we identified the hamster as a pharmacologically relevant preclinical model (IC50 = 8.2 µM). These findings provide a structural basis for the rational design of next-generation INPP5K inhibitors and establish a suitable animal model for their evaluation.