8SOE

Phosphoinositide phosphate 3 kinase gamma bound with ADP and two Gbetagamma subunits in State 2

Summary for 8SOE

• Entry DOI: 10.2210/pdb8soe/pdb
• Related: 8SO9 8SOA 8SOB 8SOC 8SOD
• EMDB information: 40650 40651 40652 40653 40654 40655
• Descriptor: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, phosphatidylinositol-4,5-bisphosphate 3-kinase, Phosphoinositide 3-kinase regulatory subunit 5, ... (5 entities in total)
• Functional Keywords: phosphoinositide 3-kinase, chemotaxis, cancer, signaling protein
• Biological source: Bos taurus (cattle); More
• Total number of polymer chains: 6
• Total formula weight: 318680.28

Authors

Chen, C.-L.,Tesmer, J.J.G. (deposition date: 2023-04-28, release date: 2024-04-03, Last modification date: 2024-09-04)

Primary citation

Chen, C.L.,Syahirah, R.,Ravala, S.K.,Yen, Y.C.,Klose, T.,Deng, Q.,Tesmer, J.J.G.
Molecular basis for G beta gamma-mediated activation of phosphoinositide 3-kinase gamma.
Nat.Struct.Mol.Biol., 31:1198-1207, 2024

PubMed Abstract: The conversion of phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-triphosphate by phosphoinositide 3-kinase γ (PI3Kγ) is critical for neutrophil chemotaxis and cancer metastasis. PI3Kγ is activated by Gβγ heterodimers released from G protein-coupled receptors responding to extracellular signals. Here we determined cryo-electron microscopy structures of Sus scrofa PI3Kγ-human Gβγ complexes in the presence of substrates/analogs, revealing two Gβγ binding sites: one on the p110γ helical domain and another on the p101 C-terminal domain. Comparison with PI3Kγ alone reveals conformational changes in the kinase domain upon Gβγ binding that are similar to Ras·GTP-induced changes. Assays of variants perturbing the Gβγ binding sites and interdomain contacts altered by Gβγ binding suggest that Gβγ recruits the enzyme to membranes and allosterically regulates activity via both sites. Studies of zebrafish neutrophil migration align with these findings, paving the way for in-depth investigation of Gβγ-mediated activation mechanisms in this enzyme family and drug development for PI3Kγ.

PubMed: 38565696
DOI: 10.1038/s41594-024-01265-y

Experimental method

ELECTRON MICROSCOPY (3.6 Å)