Inositol trisphosphate 3-kinase phosphorylates inositol 1,4,5-trisphosphate (IP3) specifically at its secondary 3-hydroxyl group to generate a tetrakisphosphate. The new paper was published in Nature Communications and is titled “Substrate promiscuity of inositol 1,4,5- trisphosphate kinase driven by structurally-modified ligands and active site plasticity”.
The authors used synthetic ligands, crystallography and fluorescence polarization binding assays using a synthetic fluorescently-tagged IP3 to interrogate enzyme specificity, which surprisingly surpasses that of its natural substrate. An active-site helix-tilt allows binding of diverse ligands even with a primary hydroxyl in the reactive cyclitol position and also those based on a glucose core. Crystallisation experiments were designed to allow reactions to proceed in situ, facilitating unequivocal characterisation of the atypical products. The work features carbohydrate ligands synthesized by Megan Shipton, a recent DPhil student from the Department, and may facilitate development of new therapeutics.
Read the article by Márquez-Moñino et al: https://www.nature.com/articles/s41467-024-45917-5