Structure of the phosphoinositide 3-kinase (PI3K) p110γ-p101 complex reveals molecular mechanism of GPCR activation

The class IB phosphoinositide 3-kinase (PI3K), PI3K gamma, is a master regulator of immune cell function and a promising drug target for both cancer and inflammatory diseases. Critical to PI3K gamma function is the association of the p110 gamma catalytic subunit to either a p101 or p84 regulatory subunit, which mediates activation by G protein-coupled receptors. Here, we report the cryo-electron microscopy structure of a heterodimeric PI3K gamma complex, p110 gamma-p101. This structure reveals a unique assembly of catalytic and regulatory subunits that is distinct from other class I PI3K complexes. p101 mediates activation through its G beta gamma-binding domain, recruiting the heterodimer to the membrane and allowing for engagement of a secondary G beta gamma-binding site in p110 gamma. Mutations at the p110 gamma-p101 and p110 gamma-adaptor binding domain interfaces enhanced G beta gamma activation. A nanobody that specifically binds to the p101-G gamma. interface blocks activation, providing a novel tool to study and target p110 gamma-p101-specific signaling events in vivo.