8SOC

Phosphoinositide phosphate 3 kinase gamma bound with ADP and Gbetagamma

8SOC の概要

• エントリーDOI: 10.2210/pdb8soc/pdb
• EMDBエントリー: 40653
• 分子名称: phosphatidylinositol-4,5-bisphosphate 3-kinase, Phosphoinositide 3-kinase regulatory subunit 5, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (5 entities in total)
• 機能のキーワード: phosphoinositide 3-kinase, chemotaxis, cancer, signaling protein
• 由来する生物種: Sus scrofa (pig); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 272589.39

構造登録者

Chen, C.-L.,Tesmer, J.J.G. (登録日: 2023-04-28, 公開日: 2024-04-03, 最終更新日: 2024-09-04)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (3.5 Å)