Yuankun Dao

All Publications

• Structural basis of insulin receptor antagonism by bivalent site 1-site 2 ligands S961 and Ins-AC-S2. Nature communications Vogel, A., Blakely, A., Dao, Y., Lin, N., Chou, D., Hill, C. P. 2026; 17 (1)

  Abstract

  Congenital hyperinsulinism is a rare genetic disease characterized by overproduction of insulin. One class of potential treatments is insulin receptor antagonists like S961 and Ins-AC-S2, which comprise segments for binding each of the two insulin-binding sites (site 1 and site 2) on the receptor. Notably, S597 - containing the same receptor binding segments as S961 but in the opposite order (site 2-site 1) - is an insulin receptor agonist rather than an antagonist. Using cryo-EM, we show how both S961 and Ins-AC-S2 bind an inactive conformation of the receptor, thereby explaining their antagonism. Furthermore, our structures reveal how agonist vs. antagonist activity is influenced by the order of site 1- and site 2-binding modules in bivalent ligands. Additionally, we show subtle differences between the receptor-binding mechanisms of S961 and Ins-AC-S2, which include displacement or engagement of alphaCT, and a binding interface between the Ins-AC-S2 insulin and the receptor FnIII-2/insert domains. These structural insights may inform development of next generation insulin receptor antagonists for treatment of congenital hyperinsulinism.

  View details for DOI 10.1038/s41467-026-73851-1

  View details for PubMedID 42265100

• Synthesis of Insulin-desB30 Analogs via an Enzymatically Removable N-Terminal Solubilizing Tag. Organic letters Dao, Y., Lin, T., Le Bich Tran, N., Griffiths Chen, F., Hung-Chieh Chou, D. 2025

  Abstract

  Chemical synthesis enables rapid access to designed insulin analogs, but the efficiency is hindered by the insulin A-chain's poor solubility. We report a streamlined route using direct Fmoc-SPPS of a native A chain aided by a temporary polylysine solubility tag removable by Lys-C under mild aqueous conditions. The workflow improves isolation, folding, and chain combination and generalizes to difficult targets (A16Pro mutant insulin, methyl-ketone A6-A11 surrogate, four-disulfide insulin), delivering high-purity products.

  View details for DOI 10.1021/acs.orglett.5c04131

  View details for PubMedID 41229176

• Structural basis of insulin receptor antagonism by bivalent site 1-site 2 ligands. bioRxiv : the preprint server for biology Vogel, A., Blakely, A., Dao, Y., Lin, N. P., Chou, D., Hill, C. P. 2025

  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.

  View details for DOI 10.1101/2025.08.23.671589

  View details for PubMedID 40894704

  View details for PubMedCentralID PMC12393571

• Modulation of insulin receptor activation through controlled folding of peptide ligands. Organic & biomolecular chemistry Li, W., Dao, Y., Lin, T., Austin, M. J., Lin, N. P., Chou, D. H. 2025

  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.

  View details for DOI 10.1039/d5ob00363f

  View details for PubMedID 40277138