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A Synthetic Polyphosphoinositide Headgroup Surrogate in Complex with SHIP2 Provides a Rationale for Drug Discovery

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journal contribution
posted on 16.12.2015 by Stephen J. Mills, Camilla Persson, Gyles Cozier, Mark P. Thomas, Lionel Trésaugues, Christophe Erneux, Andrew M. Riley, Pär Nordlund, Barry V. L. Potter
Phosphoinositides regulate many cellular processes, and cellular levels are controlled by kinases and phosphatases. SHIP2 (SH2 (Src homology 2)-domain-containing inositol-phosphatase-2) plays a critical role in phosphoinositide signaling, cleaving the 5-phosphate from phosphatidylinositol 3,4,5-trisphosphate. SHIP2 is thought to be involved in type-2 diabetes and obesity, conditions that could therefore be open to pharmacological modulation of the enzyme. However, rational design of SHIP2 inhibitors has been limited by the absence of a high-resolution structure. Here, we present a 2.1 Å resolution crystal structure of the phosphatase domain of SHIP2 bound to the synthetic ligand biphenyl 2,3′,4,5′,6-pentakisphosphate (BiPh­(2,3′,4,5′,6)­P5). BiPh­(2,3′,4,5′,6)­P5 is not a SHIP2 substrate but inhibits Ins­(1,3,4,5)­P4 hydrolysis with an IC50 of 24.8 ± 3.0 μM, (Km for Ins­(1,3,4,5)­P4 is 215 ± 28 μM). Molecular dynamics simulations suggest that when BiPh­(2,3′,4,5′,6)­P5 binds to SHIP2, a flexible loop folds over and encloses the ligand. Compounds targeting such a closed conformation might therefore deliver SHIP2-specific drugs.