{"doi":"10.1101/2022.01.22.477343","title":"The relaxin receptor RXFP1 signals through a mechanism of autoinhibition","abstract":"Abstract The relaxin family peptide receptor 1 (RXFP1) is the receptor for relaxin-2, an important regulator of reproductive and cardiovascular physiology. RXFP1 is a multi-domain G protein-coupled receptor (GPCR) with an ectodomain consisting of an LDLa module and leucine-rich repeats. The mechanism of RXFP1 signal transduction is clearly distinct from that of other GPCRs, but remains very poorly understood. Here, we present the cryo-electron microscopy structure of active-state human RXFP1, bound to a single-chain version of the endogenous agonist relaxin-2 and to the heterotrimeric G s protein. Evolutionary coupling analysis and structure-guided functional experiments reveal that RXFP1 signals through a mechanism of autoinhibition, wherein the receptor’s extracellular loop 2 occupies the orthosteric site in the active state but is inhibited by the ectodomain in the absence of relaxin-2. Our results explain how an unusual GPCR family functions, providing a path to rational drug development targeting the relaxin receptors.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":299769,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9614,"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":106139,"name":"Shaun Rawson","orcid":"0000-0002-2973-2630","position":1,"is_corresponding":false},{"id":302484,"name":"James Osei‐Owusu","orcid":"0000-0002-8676-4444","position":2,"is_corresponding":false},{"id":261649,"name":"Kelly P. Brock","orcid":"0000-0002-5236-3773","position":3,"is_corresponding":false},{"id":255563,"name":"Xinyue Liu","orcid":"0000-0002-0934-4155","position":4,"is_corresponding":false},{"id":136624,"name":"Joao A. Paulo","orcid":"0000-0002-4291-413X","position":5,"is_corresponding":false},{"id":352068,"name":"Julian Mintseris","orcid":null,"position":6,"is_corresponding":false},{"id":107041,"name":"Steven P. Gygi","orcid":"0000-0001-7626-0034","position":7,"is_corresponding":false},{"id":56406,"name":"Debora S. Marks","orcid":"0000-0001-9388-2281","position":8,"is_corresponding":false},{"id":563770,"name":"Xiaojing Cong","orcid":"0000-0002-5051-2392","position":9,"is_corresponding":false},{"id":239851,"name":"Andrew C. Kruse","orcid":"0000-0002-1467-1222","position":10,"is_corresponding":false},{"id":261648,"name":"Sarah C. Erlandson","orcid":null,"position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:31:49.412501Z","pmid":null,"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":[]}