Characterisation of an allosteric site in PLCγ enzymes and implications for development of their specific inhibitors.

ABSTRACT: Phospholipase C gamma (PLCγ) 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 PLCγ, underlying their specificity for the PLCγ family. This binding site overlaps with the PLCγ autoinhibitory interface, suggesting that the inhibitory impact of nucleotides involves stabilisation of autoinhibition. We have also analysed disease-linked variants of PLCγ1 and PLCγ2 to show that multiple mechanisms coul

SUBMITTER: Bunney TD 

PROVIDER: S-EPMC12687421 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature