{"doi":"10.1039/d5ob00363f","title":"Modulation of insulin receptor activation through controlled folding of peptide ligands","abstract":"Insulin receptor (IR) activation requires coordinated engagement of two distinct insulin-binding sites, and recent structural insights have highlighted the role of a disulfide bond in IR agonist S597 in the S597-IR complex. In this study, we synthesized and evaluated analogs of S597 and the IR antagonist Ins-AC-S2, replacing their native disulfide bridges with alternative linkages. While these modifications had minimal impact on Ins-AC-S2's antagonistic activity, they significantly reduced the agonistic potency of S597, suggesting that conformational stability is critical for receptor activation. Our findings provide a structural basis for designing non-insulin ligands to selectively activate or inhibit the insulin receptor, with potential therapeutic implications.","journal":"Organic & Biomolecular Chemistry","year":2025,"id":550424,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9573,"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":152854,"name":"Yuankun Dao","orcid":null,"position":1,"is_corresponding":false},{"id":1446019,"name":"Terra Lin","orcid":null,"position":2,"is_corresponding":false},{"id":1048017,"name":"Maxwell J. Austin","orcid":null,"position":3,"is_corresponding":false},{"id":483686,"name":"Nai-Pin Lin","orcid":null,"position":4,"is_corresponding":false},{"id":482416,"name":"Danny Hung‐Chieh Chou","orcid":"0000-0001-9110-614X","position":5,"is_corresponding":false},{"id":1445651,"name":"Wenchao Li","orcid":"0000-0001-5687-870X","position":0,"is_corresponding":true}],"reference_count":18,"raw_metadata":null,"created_at":"2026-07-19T02:54:16.596730Z","pmid":"40277138","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":[]}