{"doi":"10.1101/2023.04.28.538657","title":"Conformational dynamics of the μ-opioid receptor determine ligand intrinsic efficacy","abstract":"Abstract The μ-opioid receptor (μOR) is an important target for pain management and the molecular understanding of drug action will facilitate the development of better therapeutics. Here we show, using double electron-electron resonance (DEER) and single-molecule fluorescence resonance energy transfer (smFRET), how ligand-specific conformational changes of the μOR translate into a broad range of intrinsic efficacies at the transducer level. We identify several cytoplasmic receptor conformations interconverting on different timescales, including a pre-activated receptor conformation which is capable of G protein binding, and a fully activated conformation which dramatically lowers GDP affinity within the ternary complex. Interaction of β-arrestin-1 with the μOR core binding site appears less specific and occurs with much lower affinity than binding of G protein G i . One-Sentence Summary Ligand-dependent conformational dynamics of the μ-opioid receptor determine downstream signaling efficacy.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":391326,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9557,"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":317675,"name":"Matthias Elgeti","orcid":"0000-0002-0550-4852","position":1,"is_corresponding":false},{"id":255548,"name":"Evan S. O’Brien","orcid":"0000-0002-2260-7722","position":2,"is_corresponding":false},{"id":1164025,"name":"Cecı́lia P. Sár","orcid":null,"position":3,"is_corresponding":false},{"id":1164026,"name":"Amal EI Daibani","orcid":null,"position":4,"is_corresponding":false},{"id":984506,"name":"Jie Heng","orcid":"0000-0002-4441-1827","position":5,"is_corresponding":false},{"id":1163635,"name":"Xiaoou Sun","orcid":"0000-0002-1839-4242","position":6,"is_corresponding":false},{"id":225471,"name":"Tao Che","orcid":"0000-0002-1620-3027","position":7,"is_corresponding":false},{"id":317676,"name":"Wayne L. Hubbell","orcid":"0000-0003-0577-3312","position":8,"is_corresponding":false},{"id":251465,"name":"Brian K. Kobilka","orcid":"0000-0001-5958-3990","position":9,"is_corresponding":false},{"id":1163636,"name":"Chunlai Chen","orcid":"0000-0002-0128-7766","position":10,"is_corresponding":false},{"id":345531,"name":"Jiawei Zhao","orcid":"0000-0002-0582-2105","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T01:18:42.653719Z","pmid":"37163120","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":[]}