Abstract
Phosphatidylinositol phosphates (PIPs) are membrane phospholipids that play crucial roles in a wide range of cellular processes. Their function is dictated by the number and positions of the phosphate groups in the inositol ring (with seven different PIPs being active in the cell). Therefore, there is significant interest in developing small-molecule receptors that can bind selectively to these species and in doing so affect their cellular function or be the basis for molecular probes. However, to date there are very few examples of such molecular receptors. Towards this aim, herein we report a novel tripodal molecule that acts as receptor for mono- and bis-phosphorylated PIPs in a cell free environment. To assess their affinity to PIPs we have developed a new cell free assay based on the ability of the receptor to prevent alkaline phosphatase from hydrolysing these substrates. The new receptor displays selectivity towards two out of the seven PIPs, namely PI(3)P and PI(3,4)P2. To rationalise these results, a DFT computational study was performed which corroborated the experimental results and provided insight into the host–guest binding mode.
Highlights
Phosphatidylinositol phosphates (PIPs) are membrane phospholipids that play crucial roles in a wide range of cellular processes
The Pleckstrin Homology (PH) domain forms the largest group of recognition modules[7]
It is composed of approximately 120 amino acid residues and is present in over 270 human proteins which have been associated with a variety of processes such as intracellular signalling, membrane trafficking, cytoskeletal rearrangements and lipid metabolism
Summary
Phosphatidylinositol phosphates (PIPs) are membrane phospholipids that play crucial roles in a wide range of cellular processes. To the best of our knowledge, this is the only example of a small-molecule receptor that binds selectively to a PIP (rather than an IP) and is able to compete with protein domains in a cellular environment Inspired by these previously reported scaffolds for IP3 as well as the recognition units in our earlier work with the linear PHDM receptor, we report a new tripodal molecule (11—see Fig. 2) able to bind to PI(3)P and PI(3,4)P2 selectively over several other mono-, bi- and tri-phosphorylated PIPs in a cell free environment. The affinity and selectivity of 11 against several PIPs was studied experimentally and rationalised via DFT calculations
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