{"doi":"10.1101/2025.08.23.671589","title":"Structural basis of insulin receptor antagonism by bivalent site 1-site 2 ligands","abstract":"Congenital hyperinsulinism (HI) is a rare genetic disease characterized by overproduction of insulin. One class of potential HI treatments is insulin receptor (IR) antagonists like S961 and Ins-AC-S2, peptides composed of binding segments for each of the IR sites capable of binding insulin: site 1 and site 2. Notably, S597 - containing the same IR binding segments as S961 but in the opposite order (site 2-site 1) - is an IR agonist rather than an antagonist. Using cryo-EM, we show how both S961 and Ins-AC-S2 bind an inactive conformation of IR, thereby explaining their antagonism. Furthermore, our structures reveal how agonist vs. antagonist activity is dictated by the order of site 1- and site 2-binding modules in bivalent ligands. Additionally, we uncover subtle differences between the binding mechanisms of S961 and Ins-AC-S2 to IR, which include displacement or engagement of αCT, respectively, and a novel binding interface between the Ins-AC-S2 insulin and the receptor. These structural insights may inform development of next generation IR antagonists for treatment of HI.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":573241,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9648,"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":816866,"name":"Alan Blakely","orcid":"0000-0002-8066-7870","position":1,"is_corresponding":false},{"id":152854,"name":"Yuankun Dao","orcid":null,"position":2,"is_corresponding":false},{"id":483686,"name":"Nai-Pin Lin","orcid":null,"position":3,"is_corresponding":false},{"id":482416,"name":"Danny Hung‐Chieh Chou","orcid":"0000-0001-9110-614X","position":4,"is_corresponding":false},{"id":666493,"name":"Christopher P. Hill","orcid":"0000-0001-6796-7740","position":5,"is_corresponding":false},{"id":1480051,"name":"Arthur Vogel","orcid":"0000-0003-2165-3994","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T02:57:32.445190Z","pmid":"40894704","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":[]}