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Structure paper

TitleMolecular basis for Gβγ-mediated activation of phosphoinositide 3-kinase γ.
Journal, issue, pagesNat Struct Mol Biol, Year 2024
Publish dateApr 2, 2024
AuthorsChun-Liang Chen / Ramizah Syahirah / Sandeep K Ravala / Yu-Chen Yen / Thomas Klose / Qing Deng / John J G Tesmer /
PubMed AbstractThe 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. ...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.
External linksNat Struct Mol Biol / PubMed:38565696
MethodsEM (single particle)
Resolution3.03 - 3.9 Å
Structure data

40650

8so9

EMDB-40650, PDB-8so9:
Phosphoinositide phosphate 3 kinase gamma
Method: EM (single particle) / Resolution: 3.03 Å

40651

8soa

EMDB-40651, PDB-8soa:
Phosphoinositide phosphate 3 kinase gamma bound with ATP
Method: EM (single particle) / Resolution: 3.32 Å

40652

8sob

EMDB-40652, PDB-8sob:
Phosphoinositide phosphate 3 kinase gamma bound with ADP
Method: EM (single particle) / Resolution: 3.9 Å

40653

8soc

EMDB-40653, PDB-8soc:
Phosphoinositide phosphate 3 kinase gamma bound with ADP and Gbetagamma
Method: EM (single particle) / Resolution: 3.5 Å

40654

8sod

EMDB-40654, PDB-8sod:
Phosphoinositide phosphate 3 kinase gamma bound with ADP and two Gbetagamma subunits in State 1
Method: EM (single particle) / Resolution: 3.4 Å

40655

8soe

EMDB-40655, PDB-8soe:
Phosphoinositide phosphate 3 kinase gamma bound with ADP and two Gbetagamma subunits in State 2
Method: EM (single particle) / Resolution: 3.6 Å

Chemicals

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM / Adenosine triphosphate

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM / Adenosine diphosphate

Source
  • sus scrofa (pig)
  • bos taurus (cattle)
KeywordsSIGNALING PROTEIN / Phosphoinositide 3-Kinase / Chemotaxis / Cancer

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