{"doi":"10.1126/scisignal.adf2173","title":"Unraveling allostery within the angiotensin II type 1 receptor for Gα <sub>q</sub> and β-arrestin coupling","abstract":"G protein–coupled receptors engage both G proteins and β-arrestins, and their coupling can be biased by ligands and mutations. Here, to resolve structural elements and mechanisms underlying effector coupling to the angiotensin II (AngII) type 1 receptor (AT1R), we combined alanine scanning mutagenesis of the entire sequence of the receptor with pharmacological profiling of Gα q and β-arrestin engagement to mutant receptors and molecular dynamics simulations. We showed that Gα q coupling to AT1R involved a large number of residues spread across the receptor, whereas fewer structural regions of the receptor contributed to β-arrestin coupling regulation. Residue stretches in transmembrane domain 4 conferred β-arrestin bias and represented an important structural element in AT1R for functional selectivity. Furthermore, we identified allosteric small-molecule binding sites that were enclosed by communities of residues that produced biased signaling when mutated. Last, we showed that allosteric communication within AT1R emanating from the Gα q coupling site spread beyond the orthosteric AngII-binding site and across different regions of the receptor, including currently unresolved structural regions. Our findings reveal structural elements and mechanisms within AT1R that bias Gα q and β-arrestin coupling and that could be harnessed to design biased receptors for research purposes and to develop allosteric modulators.","journal":"Science Signaling","year":2023,"id":326246,"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":29,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9485,"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":226896,"name":"Wijnand J. C. van der Velden","orcid":"0000-0003-0785-3762","position":1,"is_corresponding":false},{"id":671003,"name":"Yoon Namkung","orcid":"0000-0002-3085-2066","position":2,"is_corresponding":false},{"id":680268,"name":"Anita K. Nivedha","orcid":"0000-0001-5272-7445","position":3,"is_corresponding":false},{"id":858496,"name":"Aaron Cho","orcid":null,"position":4,"is_corresponding":false},{"id":1045141,"name":"Dana Sedki","orcid":"0000-0002-4264-5769","position":5,"is_corresponding":false},{"id":1045142,"name":"Brian J. Holleran","orcid":"0000-0003-3136-1928","position":6,"is_corresponding":false},{"id":1045143,"name":"N H Lee","orcid":"0000-0002-6494-0849","position":7,"is_corresponding":false},{"id":805732,"name":"Richard Leduc","orcid":"0000-0001-6854-8003","position":8,"is_corresponding":false},{"id":1045144,"name":"Sanychen Muk","orcid":"0000-0002-3490-8143","position":9,"is_corresponding":false},{"id":1045811,"name":"Keith Le","orcid":null,"position":10,"is_corresponding":false},{"id":434047,"name":"S. Bhattacharya","orcid":"0000-0003-0483-2149","position":11,"is_corresponding":false},{"id":272488,"name":"Nagarajan Vaidehi","orcid":"0000-0001-8100-8132","position":12,"is_corresponding":false},{"id":611026,"name":"Stéphane A. Laporte","orcid":"0000-0002-0633-543X","position":13,"is_corresponding":false},{"id":1036143,"name":"Yubo Cao","orcid":"0000-0002-9085-1153","position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":null,"created_at":"2026-07-19T01:08:33.106703Z","pmid":"37552769","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":[]}