{"doi":"10.1101/2025.06.30.662233","title":"Ligand-dependent G protein dynamics underlying opioid signaling efficacy","abstract":"Activation of heterotrimeric G proteins by G protein-coupled receptors (GPCRs) requires large-scale opening of the Gα α-helical domain (AHD) to expose the nucleotide-binding site and facilitate GDP-GTP exchange. While orthosteric ligands are known to modulate GPCR conformation and signaling efficacy, how these effects propagate to the G protein itself remains unclear. Using single-molecule fluorescence resonance energy transfer (smFRET) imaging, we monitored AHD motions in Gi proteins coupled to the μ-opioid receptor (μOR) across a spectrum of ligand- and nucleotide-bound states. We find that receptor ligands differentially modulate these dynamics from over 70 angstrom away, with higher-efficacy agonists more effectively promoting transitions to an open, low-nucleotide-affinity conformation. These data also capture transient μOR-Gi intermediates during nucleotide binding and suggest that μ-opioid ligand efficacy arises in part from allosteric control over G protein conformational equilibria that kinetically gate activation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":556505,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9628,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":255545,"name":"Daniel Hilger","orcid":"0000-0001-5179-1357","position":1,"is_corresponding":false},{"id":690841,"name":"John Janetzko","orcid":"0000-0003-1604-2515","position":2,"is_corresponding":false},{"id":560921,"name":"Charles E. Schroeder","orcid":"0000-0001-6023-2274","position":3,"is_corresponding":false},{"id":236408,"name":"Steven Chu","orcid":"0000-0002-4572-0154","position":4,"is_corresponding":false},{"id":251465,"name":"Brian K. Kobilka","orcid":"0000-0001-5958-3990","position":5,"is_corresponding":false},{"id":802248,"name":"Rabindra V. Shivnaraine","orcid":null,"position":6,"is_corresponding":false},{"id":476214,"name":"Jonathan Deutsch","orcid":null,"position":0,"is_corresponding":true}],"reference_count":86,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:08.896385Z","pmid":"40631176","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":[]}