Phosphatidylinositides are one family of the most versatile signaling molecules in cells, yet how they interact with different proteins to regulate biological processes is not well understood. Towards a general strategy to identify phosphatidylinositide–protein interactions, a fluorous diazirine group has been incorporated into phosphatidylinositol 4,5-bisphosphate (PIP₂). The modified PIP₂ was effectively cleaved by phospholipase C, one signaling protein that utilizes PIP₂ as its endogenous substrate. Upon light illumination, the PIP₂ probe effectively crosslinks with small GTPase ADP-ribosylation 1 to form a complex, suggesting that the probe might be suitable to identify PIP₂-interacting proteins on the proteome level.