7MEZ

Structure of the phosphoinositide 3-kinase p110 gamma (PIK3CG) p101 (PIK3R5) complex

Summary for 7MEZ

• Entry DOI: 10.2210/pdb7mez/pdb
• EMDB information: 23808
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, Phosphoinositide 3-kinase regulatory subunit 5 (2 entities in total)
• Functional Keywords: pi3k, p110, pik3cg, pik3r5, p101, phosphoinositide 3-kinase, pip3, immune system, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 224099.21

Authors

Burke, J.E.,Dalwadi, U.,Rathinaswamy, M.K.,Yip, C.K. (deposition date: 2021-04-08, release date: 2021-07-14, Last modification date: 2024-05-29)

Primary citation

Rathinaswamy, M.K.,Dalwadi, U.,Fleming, K.D.,Adams, C.,Stariha, J.T.B.,Pardon, E.,Baek, M.,Vadas, O.,DiMaio, F.,Steyaert, J.,Hansen, S.D.,Yip, C.K.,Burke, J.E.
Structure of the phosphoinositide 3-kinase (PI3K) p110 gamma-p101 complex reveals molecular mechanism of GPCR activation.
Sci Adv, 7:-, 2021

PubMed Abstract: The class IB phosphoinositide 3-kinase (PI3K), PI3Kγ, is a master regulator of immune cell function and a promising drug target for both cancer and inflammatory diseases. Critical to PI3Kγ function is the association of the p110γ 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 PI3Kγ complex, p110γ-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 Gβγ-binding domain, recruiting the heterodimer to the membrane and allowing for engagement of a secondary Gβγ-binding site in p110γ. Mutations at the p110γ-p101 and p110γ-adaptor binding domain interfaces enhanced Gβγ activation. A nanobody that specifically binds to the p101-Gβγ interface blocks activation, providing a novel tool to study and target p110γ-p101-specific signaling events in vivo.

PubMed: 34452907
DOI: 10.1126/sciadv.abj4282

Experimental method

ELECTRON MICROSCOPY (2.89 Å)