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Publication Abstract from PubMed

Phospholipase C gamma (PLCgamma) enzymes are key components of intracellular signal transduction processes and are involved in disease development, including immune dysregulation, specific cancer types and neurodegeneration. Although recognised as important targets for intervention, validated pharmacological tools are lacking. Here, we demonstrate that inhibitory nucleotides bind directly to an allosteric site at the interface between the PLC-core and regulatory-array unique for PLCgamma, underlying their specificity for the PLCgamma family. This binding site overlaps with the PLCgamma autoinhibitory interface, suggesting that the inhibitory impact of nucleotides involves stabilisation of autoinhibition. We have also analysed disease-linked variants of PLCgamma1 and PLCgamma2 to show that multiple mechanisms could underpin their gain-of-function phenotype. While the sensitivity of these variants to physiological nucleotide inhibition is reduced, we identified artificial nucleotide compounds that can inhibit such variants not only in vitro but also in cell-based assays. Therefore, our findings suggest a route for development of isozyme specific PLCgamma inhibitors allowing further studies of their roles in health and disease.

Characterisation of an allosteric site in PLCgamma enzymes and implications for development of their specific inhibitors.,Bunney TD, Nyvall HG, Macrae C, Lalovic D, Gregory A, Le Huray KIP, Harvey N, Pinotsis N, Kalli AC, Waudby CA, Burke JE, Katan M Biochem J. 2025 Oct 16;482(20):BCJ20253358. doi: 10.1042/BCJ20253358. PMID:41002943^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.