SH2-containing-inositol-5-phosphatases (INPP5D); A Target Enabling Package

SH2-containing-inositol-5-phosphatases (SHIP1 and SHIP2, coded for by genes INPP5D and INPPL1, respectively) dephosphorylate phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) to produce phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2). This is an important part of the PI3K/AKT/mTOR signalling pathway. The SHIPs have been linked to a range of conditions, including cancer, diabetes, hypertension, and graft versus host disease. A link has also been demonstrated by GWAS between a non-coding mutation in the INPP5D (SHIP1) gene and increased risk of late-onset Alzheimer’s disease. The role of SHIP1 in Alzheimer’s disease is believed to be mediated through inflammatory processes such as the regulation of microglia and cytokine release. The distinction between the effects of SHIP1 and SHIP2 on these processes is not fully understood. In this TEP we present an apo structure of the phosphatase and C2 domains of SHIP1 and a structure with a magnesium ion and a phosphate ion bound to the active site. We also present 91 fragment bound structures that may act as starting points for the modulation of SHIP1. We are also able to crystallise an equivalent construct of SHIP2 and purify a range of other inositol-5-phosphatases to serve as a selectivity panel for the development of specific compounds. An assay has also been developed.