9qb7 | pdb_00009qb7

Structure of rat Phospholipase C gamma 1 mutant S345F

spinqualitylabelsall models 9qb7, resolution 2.56Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9qb7 is a 1 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.56Å Ligands: SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PLCG1_RAT Mediates the production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). Plays an important role in the regulation of intracellular signaling cascades. Becomes activated in response to ligand-mediated activation of receptor-type tyrosine kinases, such as PDGFRA, PDGFRB, FGFR1, FGFR2, FGFR3 and FGFR4. Plays a role in actin reorganization and cell migration (By similarity). 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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