{"doi":"10.1073/pnas.2407574122","title":"Prolonged signaling of backbone-modified glucagon‐like peptide‐ <b>1</b> analogues with diverse receptor trafficking","abstract":"Signal duration and subcellular location are emerging as important facets of G protein–coupled receptor (GPCR) function. The glucagon-like peptide-1 receptor (GLP-1R), a clinically relevant class B1 GPCR, stimulates production of the second messenger cyclic adenosine monophosphate (cAMP) upon activation by the native hormone, GLP-1. cAMP production continues after the hormone–receptor complex has been internalized via endocytosis. Here, we report GLP-1 analogues that induce prolonged signaling relative to GLP-1. A single β-amino acid substitution at position 18, with the residue derived from ( S , S )- trans -2-aminocyclopentanecarboxylic acid (ACPC), enhances signaling duration with retention of receptor endocytosis. Pairing ACPC at position 18 with a second substitution, α-aminoisobutyric acid (Aib) at position 16, abrogates endocytosis, but prolonged signaling is maintained. Prolonged signaling is sensitive to the structure of the β residue at position 18. Cryoelectron microscopy structures of two GLP-1 analogues bound to the GLP-1R:Gs complex suggest substantial alterations to bound peptide structure and dynamics compared to the GLP-1:GLP-1R:Gs complex. These structural findings strengthen an emerging view that agonist dynamics in the receptor-bound state influence signaling profiles. Our results advance understanding of the structural underpinnings of receptor activation and introduce tools for exploring the impact of spatiotemporal signaling profiles following GLP-1R activation.","journal":"Proceedings of the National Academy of Sciences","year":2025,"id":518147,"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":0.9601,"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":1107641,"name":"Marlies V. Hager","orcid":"0000-0001-8050-4943","position":1,"is_corresponding":false},{"id":1370957,"name":"Zamara Mariam","orcid":"0000-0002-4563-9559","position":2,"is_corresponding":false},{"id":1072060,"name":"Rylie K. Morris","orcid":"0000-0001-5305-6006","position":3,"is_corresponding":false},{"id":307914,"name":"Matthew J. Belousoff","orcid":"0000-0002-3229-474X","position":4,"is_corresponding":false},{"id":307911,"name":"Giuseppe Deganutti","orcid":"0000-0001-8780-2986","position":5,"is_corresponding":false},{"id":307922,"name":"Patrick M. Sexton","orcid":"0000-0001-8902-2473","position":6,"is_corresponding":false},{"id":307921,"name":"Denise Wootten","orcid":"0000-0003-4563-1642","position":7,"is_corresponding":false},{"id":294605,"name":"Samuel H. Gellman","orcid":"0000-0001-5617-0058","position":8,"is_corresponding":false},{"id":657126,"name":"Brian P. Cary","orcid":"0000-0001-9523-2522","position":0,"is_corresponding":true}],"reference_count":86,"raw_metadata":null,"created_at":"2026-07-19T02:49:04.756302Z","pmid":"40168114","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":[]}