{"doi":"10.1101/2021.06.01.446612","title":"Structure of the phosphoinositide 3-kinase p110γ-p101 complex reveals molecular mechanism of GPCR activation","abstract":"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 (GPCRs). Here, we report the cryo-EM 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. Multiple oncogenic mutations mapped to these novel interfaces and 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 .","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":225244,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9518,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":614122,"name":"Udit Dalwadi","orcid":"0000-0001-7887-7070","position":1,"is_corresponding":false},{"id":586068,"name":"Kaelin D. Fleming","orcid":"0000-0003-3063-7865","position":2,"is_corresponding":false},{"id":507081,"name":"Carson Adams","orcid":"0000-0002-0000-711X","position":3,"is_corresponding":false},{"id":653788,"name":"Jordan TB Stariha","orcid":"0000-0002-9501-3722","position":4,"is_corresponding":false},{"id":263120,"name":"Els Pardon","orcid":"0000-0002-2466-0172","position":5,"is_corresponding":false},{"id":614112,"name":"Minkyung Baek","orcid":"0000-0003-3414-9404","position":6,"is_corresponding":false},{"id":653789,"name":"Oscar Vadas","orcid":"0000-0003-3511-6479","position":7,"is_corresponding":false},{"id":246362,"name":"Frank DiMaio","orcid":"0000-0002-7524-8938","position":8,"is_corresponding":false},{"id":263123,"name":"Jan Steyaert","orcid":"0000-0002-3825-874X","position":9,"is_corresponding":false},{"id":653790,"name":"Scott D. Hansen","orcid":"0000-0001-7005-6200","position":10,"is_corresponding":false},{"id":614123,"name":"Calvin K. Yip","orcid":"0000-0003-1779-9501","position":11,"is_corresponding":false},{"id":245413,"name":"John E. Burke","orcid":"0000-0001-7904-9859","position":12,"is_corresponding":false},{"id":614121,"name":"Manoj Kumar Rathinaswamy","orcid":"0000-0001-5584-4313","position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:54:26.581453Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}