8dp0

Structure of p110 gamma bound to the Ras inhibitory nanobody NB7Structure of p110 gamma bound to the Ras inhibitory nanobody NB7

Structural highlights 8dp0 is a 2 chain structure with sequence from Homo sapiens and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.96Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed PI3Kgamma is a critical immune signaling enzyme activated downstream of diverse cell surface molecules, including Ras, PKCbeta activated by the IgE receptor, and Gbetagamma subunits released from activated GPCRs. PI3Kgamma can form two distinct complexes, with the p110gamma catalytic subunit binding to either a p101 or p84 regulatory subunit, with these complexes being differentially activated by upstream stimuli. Here, using a combination of cryo electron microscopy, HDX-MS, and biochemical assays, we have identified novel roles of the helical domain of p110gamma in regulating lipid kinase activity of distinct PI3Kgamma complexes. We defined the molecular basis for how an allosteric inhibitory nanobody potently inhibits kinase activity through rigidifying the helical domain and regulatory motif of the kinase domain. The nanobody did not block either p110gamma membrane recruitment or Ras/Gbetagamma binding, but instead decreased ATP turnover. We also identified that p110gamma can be activated by dual PKCbeta helical domain phosphorylation leading to partial unfolding of an N-terminal region of the helical domain. PKCbeta phosphorylation is selective for p110gamma-p84 compared to p110gamma-p101, driven by differential dynamics of the helical domain of these different complexes. Nanobody binding prevented PKCbeta-mediated phosphorylation. Overall, this work shows an unexpected allosteric regulatory role of the helical domain of p110gamma that is distinct between p110gamma-p84 and p110gamma-p101 and reveals how this can be modulated by either phosphorylation or allosteric inhibitory binding partners. This opens possibilities of future allosteric inhibitor development for therapeutic intervention. Allosteric activation or inhibition of PI3Kgamma mediated through conformational changes in the p110gamma helical domain.,Harris NJ, Jenkins ML, Nam SE, Rathinaswamy MK, Parson MAH, Ranga-Prasad H, Dalwadi U, Moeller BE, Sheeky E, Hansen SD, Yip CK, Burke JE Elife. 2023 Jul 7;12:RP88058. doi: 10.7554/eLife.88058. PMID:37417733 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phosphoinositide 3-kinase 3D structures

spinqualitylabelsall models 8dp0, resolution 2.96Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image