{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T15:27:22Z","timestamp":1779895642046,"version":"3.53.1"},"reference-count":12,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T00:00:00Z","timestamp":1758758400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T00:00:00Z","timestamp":1758758400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["12375352"],"award-info":[{"award-number":["12375352"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"YRD Collaborative Fundamental Research Project","award":["2024CSJZN0800"],"award-info":[{"award-number":["2024CSJZN0800"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-025-07243-8","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T13:32:47Z","timestamp":1758807167000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["X-ray crystallography reveals insulin lisargine structure and mechanisms of glucose regulation"],"prefix":"10.1038","volume":"15","author":[{"given":"Zhu","family":"Zhu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiming","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingrong","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhou","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,25]]},"reference":[{"key":"7243_CR1","doi-asserted-by":"crossref","unstructured":"Ciszak, E. et al. \u2018Role of C-Terminal B-Chain Residues in Insulin Assembly: The Structure of Hexameric LysB28ProB29-Human Insulin\u2019. Structure (London, England: 1993) 3 (6): 615\u201322. (1995).","DOI":"10.1016\/S0969-2126(01)00195-2"},{"issue":"1","key":"7243_CR2","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1186\/s12906-020-03110-3","volume":"20","author":"J Lu","year":"2020","unstructured":"Lu, J. et al. Pharmacodynamics and pharmacokinetics of a new type of Recombinant insulin lisargine injection. BMC Complement. Med. Ther. 20 (1), 334 (2020).","journal-title":"BMC Complement. Med. Ther."},{"key":"7243_CR3","doi-asserted-by":"crossref","unstructured":"Huang, B. et al. Protein Structure Prediction: Challenges, Advances, and the Shift of Research Paradigms (Genomics, Proteomics & Bioinformatics, 2023).","DOI":"10.1016\/j.gpb.2022.11.014"},{"key":"7243_CR4","doi-asserted-by":"crossref","unstructured":"Jarosinski, M. A., Dhayalan, B., Chen, Y. S., Chatterjee, D. & Varas Nicol\u00e1s and Michael A. Weiss. \u2018Structural Principles of Insulin Formulation and Analog Design: A Century of Innovation\u2019. Molecular Metabolism 52 (October): 101325. (2021).","DOI":"10.1016\/j.molmet.2021.101325"},{"issue":"6","key":"7243_CR5","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1007\/s13238-010-0069-z","volume":"1","author":"Q Hua","year":"2010","unstructured":"Hua, Q. Insulin: A small protein with a long journey. Protein Cell. 1 (6), 537\u2013551 (2010).","journal-title":"Protein Cell."},{"issue":"Pt 1","key":"7243_CR6","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1107\/S090744490705024X","volume":"64","author":"TC Terwilliger","year":"2008","unstructured":"Terwilliger, T. C. et al. Iterative model building, structure refinement and density modification with the PHENIX autobuild Wizard. Acta Crystallogr. D. 64 (Pt 1), 61\u201369 (2008).","journal-title":"Acta Crystallogr. D"},{"issue":"S1","key":"7243_CR7","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1111\/dom.14552","volume":"24","author":"R Retnakaran","year":"2022","unstructured":"Retnakaran, R. & Bernard Zinman The ongoing evolution of basal insulin therapy over 100 years and its promise for the future. Diabetes Obes. Metabolism. 24 (S1), 17\u201326 (2022).","journal-title":"Diabetes Obes. Metabolism"},{"key":"7243_CR8","doi-asserted-by":"crossref","unstructured":"Varanko, A., Saha, S. & Chilkoti, A. \u2018Recent Trends in Protein and Peptide-Based Biomaterials for Advanced Drug Delivery\u2019. Advanced Drug Delivery Reviews, Advanced Drug Delivery 2020 - Part 1: Carriers for Advanced Drug Delivery, 156 (January): 133\u201387. (2020).","DOI":"10.1016\/j.addr.2020.08.008"},{"key":"7243_CR9","doi-asserted-by":"crossref","unstructured":"Caballero-P\u00e9rez, A. Jos\u00e9 Mar\u00eda Viader-Salvad\u00f3, Ana Luc\u00eda Herrera-Estala, Jos\u00e9 Antonio Fuentes-Garibay, and Martha Guerrero-Olazar\u00e1n.  Buried Kex2 sites in glargine precursor aggregates prevent its intracellular processing in Pichia pastoris Muts strains and the effect of Methanol-Feeding strategy and induction temperature on glargine precursor production parameters. Applied Biochem. Biotechnology 193 (9), 2806\u20132829 (2021).","DOI":"10.1007\/s12010-021-03567-z"},{"issue":"8","key":"7243_CR10","doi-asserted-by":"publisher","first-page":"3061","DOI":"10.1007\/s00253-021-11224-y","volume":"105","author":"P Hazra","year":"2021","unstructured":"Hazra, P. et al. A novel peptide design aids in the expression and its simplified process of manufacturing of insulin glargine in Pichia pastoris. Appl. Microbiol. Biotechnol. 105 (8), 3061\u20133074 (2021).","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"7243_CR11","doi-asserted-by":"publisher","first-page":"e0172600","DOI":"10.1371\/journal.pone.0172600","volume":"12","author":"D Mikiewicz","year":"2017","unstructured":"Mikiewicz, D. et al. Soluble insulin analogs combining rapid- and long-acting hypoglycemic properties \u2013 from an efficient E. coli expression system to a pharmaceutical formulation. PLOS ONE. 12, e0172600 (2017).","journal-title":"PLOS ONE"},{"key":"7243_CR12","doi-asserted-by":"publisher","first-page":"16818","DOI":"10.1074\/jbc.RA118.004852","volume":"293","author":"M Chrudinov\u00e1","year":"2018","unstructured":"Chrudinov\u00e1, M. et al. A versatile insulin analog with high potency for both insulin and insulin-like growth factor 1 receptors: structural implications for receptor binding. J. Biol. Chem. 293, 16818\u201316829 (2018).","journal-title":"J. Biol. Chem."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-07243-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-07243-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-07243-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T13:32:55Z","timestamp":1758807175000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-07243-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,25]]},"references-count":12,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["7243"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-07243-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,25]]},"assertion":[{"value":"6 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 June 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 September 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"We confirm that this study was reported in accordance with the ARRIVE guidelines ().","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Reporting statement"}}],"article-number":"32846"}}