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A collaborative chemical biology study from the Potter Group, with the Gonzalez Group at CSIC Madrid, deepens understanding of an enzyme acting upon a crucial cellular messenger.

Co-crystallisation of structurally modified inositol polyphosphates and related carbohydrate-based surrogates with inositol 1,4,5 trisphosphate 3-kinase:  left-hand panel shows the range of synthetically-modified ligands employed and right-hand panel shows an ensemble of co-crystal structures, showing also associated movements in an active site helix; centre panel shows the standard enzyme reaction.

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

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