{"doi":"10.1126/sciadv.abn8063","title":"Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias","abstract":"Both CXC chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) are activated by the chemokine CXCL12 yet evoke distinct cellular responses. CXCR4 is a canonical G protein-coupled receptor (GPCR), whereas ACKR3 is intrinsically biased for arrestin. The molecular basis for this difference is not understood. Here, we describe cryo-EM structures of ACKR3 in complex with CXCL12, a more potent CXCL12 variant, and a small-molecule agonist. The bound chemokines adopt an unexpected pose relative to those established for CXCR4 and observed in other receptor-chemokine complexes. Along with functional studies, these structures provide insight into the ligand-binding promiscuity of ACKR3, why it fails to couple to G proteins, and its bias toward β-arrestin. The results lay the groundwork for understanding the physiological interplay of ACKR3 with other GPCRs.","journal":"Science Advances","year":2022,"id":235079,"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":86,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.955,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":613044,"name":"Christopher T. Schafer","orcid":"0000-0001-9907-295X","position":1,"is_corresponding":false},{"id":510142,"name":"Martin Gustavsson","orcid":"0000-0002-3015-2043","position":2,"is_corresponding":false},{"id":852556,"name":"S.A. Eberle","orcid":"0000-0001-9837-6222","position":3,"is_corresponding":false},{"id":821995,"name":"Pawel K. Dominik","orcid":null,"position":4,"is_corresponding":false},{"id":852557,"name":"Dawid Deneka","orcid":"0000-0001-9472-0663","position":5,"is_corresponding":false},{"id":852558,"name":"Penglie Zhang","orcid":"0000-0001-6941-4357","position":6,"is_corresponding":false},{"id":853640,"name":"Thomas J. Schall","orcid":null,"position":7,"is_corresponding":false},{"id":260362,"name":"Anthony A. Kossiakoff","orcid":"0000-0003-3174-9359","position":8,"is_corresponding":false},{"id":254635,"name":"J.J.G. Tesmer","orcid":"0000-0003-1125-3727","position":9,"is_corresponding":false},{"id":354099,"name":"Tracy M. Handel","orcid":"0000-0002-2558-6138","position":10,"is_corresponding":false},{"id":733573,"name":"Yu‐Chen Yen","orcid":"0000-0003-4308-9167","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T00:21:48.116752Z","pmid":"35857509","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":[]}