{"doi":"10.1073/pnas.2215916120","title":"Elucidation of a dynamic interplay between a beta-2 adrenergic receptor, its agonist, and stimulatory G protein","abstract":"G protein-coupled receptors (GPCRs) represent the largest group of membrane receptors for transmembrane signal transduction. Ligand-induced activation of GPCRs triggers G protein activation followed by various signaling cascades. Understanding the structural and energetic determinants of ligand binding to GPCRs and GPCRs to G proteins is crucial to the design of pharmacological treatments targeting specific conformations of these proteins to precisely control their signaling properties. In this study, we focused on interactions of a prototypical GPCR, beta-2 adrenergic receptor (β 2 AR), with its endogenous agonist, norepinephrine (NE), and the stimulatory G protein (G s ). Using molecular dynamics (MD) simulations, we demonstrated the stabilization of cationic NE, NE(+), binding to β 2 AR by G s protein recruitment, in line with experimental observations. We also captured the partial dissociation of the ligand from β 2 AR and the conformational interconversions of G s between closed and open conformations in the NE(+)–β 2 AR–G s ternary complex while it is still bound to the receptor. The variation of NE(+) binding poses was found to alter G s α subunit (G s α) conformational transitions. Our simulations showed that the interdomain movement and the stacking of G s α α1 and α5 helices are significant for increasing the distance between the G s α and β 2 AR, which may indicate a partial dissociation of G s α The distance increase commences when G s α is predominantly in an open state and can be triggered by the intracellular loop 3 (ICL3) of β 2 AR interacting with G s α, causing conformational changes of the α5 helix. Our results help explain molecular mechanisms of ligand and GPCR-mediated modulation of G protein activation.","journal":"Proceedings of the National Academy of Sciences","year":2023,"id":327581,"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":25,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":294212,"name":"John R.D. Dawson","orcid":"0000-0002-3169-4768","position":1,"is_corresponding":false},{"id":294209,"name":"Kevin R. DeMarco","orcid":"0000-0001-6581-2497","position":2,"is_corresponding":false},{"id":1048238,"name":"Kyle C. Rouen","orcid":"0000-0001-8684-0614","position":3,"is_corresponding":false},{"id":294213,"name":"Slava Bekker","orcid":"0000-0002-8014-7023","position":4,"is_corresponding":false},{"id":249827,"name":"Vladimir Yarov‐Yarovoy","orcid":"0000-0002-2325-4834","position":5,"is_corresponding":false},{"id":294215,"name":"Colleen E. Clancy","orcid":"0000-0001-6849-4885","position":6,"is_corresponding":false},{"id":329346,"name":"Yang K. Xiang","orcid":"0000-0003-1786-9143","position":7,"is_corresponding":false},{"id":48172,"name":"Igor Vorobyov","orcid":"0000-0002-4767-5297","position":8,"is_corresponding":false},{"id":762239,"name":"Yanxiao Han","orcid":"0000-0002-1684-6073","position":0,"is_corresponding":true}],"reference_count":93,"raw_metadata":null,"created_at":"2026-07-19T01:08:47.581262Z","pmid":"36853938","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":[]}