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

Rathinaswamy, Manoj K.; Dalwadi, Udit; Fleming, Kaelin D.; Adams, Carson; Stariha, Jordan B.; Pardon, Els; Baek, Minkyung; Vadas, Oscar; DiMaio, Frank; Steyaert, Jan; Hansen, Scott D.; Yip, Calvin K.; Burke, John E.

doi:10.1126/sciadv.abj4282

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

Journal Article · 26 August 2021 · Science Advances

DOI: https://doi.org/10.1126/sciadv.abj4282 · OSTI ID:1903930

^[1]; Dalwadi, Udit ^[2];

^[3]; Adams, Carson ^[4];

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University of Victoria, BC (Canada); OSTI
University of British Columbia, Vancouver, BC (Canada)
University of Victoria, BC (Canada)
University of Washington, Seattle, WA (United States)
Vrije Universiteit Brussel (VUB), Brussels (Belgium)
University of Geneva (Switzerland)
University of Oregon, Eugene, OR (United States)
University of Victoria, BC (Canada); University of British Columbia, Vancouver, BC (Canada)

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.

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Research Organization:: University of Washington, Seattle, WA (United States)

Sponsoring Organization:: Canadian Institute of Health Research (CIHR); Cancer Research Society; European Strategy Forum on Research Infrastructures (ESFRI); Michael Smith Foundation for Health Research (MSFHR); National Institutes of Health (NIH); National Science Foundation (NSF); Natural Sciences and Engineering Research Council of Canada; Research Foundation–Flanders (FWO); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 1903930

Journal Information:: Science Advances, Journal Name: Science Advances Journal Issue: 35 Vol. 7; ISSN 2375-2548

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

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