{"doi":"10.1101/2025.09.10.675278","title":"The role of intrinsically disordered domains in regulating G protein coupled receptor signaling","abstract":"Abstract The α 2A adrenergic receptor (α 2A AR) is a clinically important target for various diseases including hypertension, diabetes and chronic pain. Here, using single-molecule fluorescence resonance energy transfer imaging, we show how agonist-specific activation dynamics in both structured transmembrane domain (TMD) and intrinsically disorders regions (IDRs) of α 2A AR lead to diverse signaling profiles. Through seven pairs of strategically designed fluorophore labels, we systematically investigate the real-time conformational changes of α 2A AR. Our study reveals unique TM6 dynamics in α 2A AR, featured by a high energy barrier for agonist-induced outward movements essential for activation. In contrast, we identify agonist-specific conformational dynamics of a partially disordered extracellular loop (ECL2), highlighting its role as a dynamic regulatory module that controls receptor function. Moreover, we characterize the conformational landscapes of the long third intracellular loop (ICL3), revealing its compact structural features and membrane-proximal localization in the basal state, where it acts as a negative allosteric regulator in transducer coupling. Furthermore, we identify multiful functional sub-states of ICL3 that are dynamically modulated by both kinase phosphorylation and drug efficacy. These findings offer previously underappreciated structural and dynamic insights into α 2A AR function governed by both TMD and IDRs, and may open up new avenues for the development of better therapeutics.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":559017,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9559,"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":547115,"name":"Ruoyi Qiu","orcid":"0000-0001-9484-4375","position":1,"is_corresponding":false},{"id":1391699,"name":"Alexander M. Garces","orcid":"0000-0003-0160-2487","position":2,"is_corresponding":false},{"id":349029,"name":"Harald Hübner","orcid":"0000-0002-7892-599X","position":3,"is_corresponding":false},{"id":1327500,"name":"Xinyu Xu","orcid":"0000-0001-9375-9742","position":4,"is_corresponding":false},{"id":349030,"name":"Dorothée Weikert","orcid":"0000-0003-2259-9002","position":5,"is_corresponding":false},{"id":349033,"name":"Peter Gmeiner","orcid":"0000-0002-4127-197X","position":6,"is_corresponding":false},{"id":255552,"name":"Michael T. Lerch","orcid":"0000-0002-8173-4879","position":7,"is_corresponding":false},{"id":251465,"name":"Brian K. Kobilka","orcid":"0000-0001-5958-3990","position":8,"is_corresponding":false},{"id":345528,"name":"Jun Xu","orcid":"0000-0002-1600-583X","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T02:55:30.312295Z","pmid":"40964316","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":[]}