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Publication explores the mechanism by which the C2 domain of SHIP1 is able to modulate inositol 5-phosphatase activity, providing insights into potential methods of targeting the protein to understand its role in Alzheimer’s disease.

SHIP1 target

SHIP1 (INPP5D) is a potentially promising target in Alzheimer’s disease. The inositol 5-phosphatase plays a central role in cellular signalling pathways and has been linked to neuroinflammation. The C2 domain of SHIP1 and the related SHIP2 modulates the activity of the phosphatase domain. While the allosteric mechanism has previously been studied in SHIP2, there are notable differences between the two proteins that cast doubt on how well this mechanism translates to SHIP1. A new paper from the CMD presents apo- and magnesium and phosphate-bound structures of the phosphatase and C2 domains of SHIP1. Bradshaw et al. go on to use activity assays, hydrogen-deuterium-exchange mass spectrometry and molecular dynamics to explore the differences in allostery in the two SHIPs. They also present a crystallographic fragment screen on SHIP1 with 91 compounds bound and a mass spectrometry screen with four follow up structures providing new avenues for the development of small molecule modulators of SHIP1.