{"doi":"10.1101/2021.02.24.432589","title":"Structural and Functional Diversity among Agonist-Bound States of the GLP-1 Receptor","abstract":"ABSTRACT Recent advances in G protein-coupled receptor (GPCR) structural elucidation have strengthened previous hypotheses that multi-dimensional signal propagation mediated by these receptors is, in part, dependent on their conformational mobility. However, the relationship between receptor function and static structures determined via crystallography or cryo-electron microscopy is not always clear. This study examines the contribution of peptide agonist conformational plasticity to activation of the glucagon-like peptide-1 receptor (GLP-1R), an important clinical target. We employ variants of the peptides GLP-1 and exendin-4 to explore the interplay between helical propensity near the agonist N-terminus and the ability to bind to and activate the receptor. Cryo-EM analysis of a complex involving an exendin-4 analogue, the GLP-1R and G s protein revealed two receptor conformers with distinct modes of peptide-receptor engagement. Our functional and structural data suggest that receptor conformational dynamics associated with flexibility of the peptide N-terminal activation domain may be a key determinant of agonist efficacy.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":215348,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9411,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":657127,"name":"Peishen Zhao","orcid":"0000-0003-0185-0595","position":1,"is_corresponding":false},{"id":657827,"name":"Tin T. Truong","orcid":null,"position":2,"is_corresponding":false},{"id":307912,"name":"Sarah Piper","orcid":"0000-0001-5337-5197","position":3,"is_corresponding":false},{"id":307914,"name":"Matthew J. Belousoff","orcid":"0000-0002-3229-474X","position":4,"is_corresponding":false},{"id":307920,"name":"Radostin Danev","orcid":"0000-0001-6406-8993","position":5,"is_corresponding":false},{"id":810097,"name":"Patrick M. Sexton","orcid":"0000-0002-6813-1336","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":80,"raw_metadata":null,"created_at":"2026-07-18T23:52:55.971300Z","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":[]}