9NCO
IN-ML-15 bound to IGF1Rzip
Summary for 9NCO
| Entry DOI | 10.2210/pdb9nco/pdb |
| EMDB information | 49261 |
| Descriptor | Insulin-like growth factor 1 receptor, IN-ML-15 beta, IN-ML-15 alpha (3 entities in total) |
| Functional Keywords | igf receptor, insulin-like growth factor, insulin, igf, signaling protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 210364.97 |
| Authors | Kirk, N.S. (deposition date: 2025-02-16, release date: 2026-02-18, Last modification date: 2026-09-02) |
| Primary citation | Selicharova, I.,Kirk, N.S.,Kertisova, A.,Lubos, M.,Mitrova, K.,Tichackova, T.,Zakova, L.,Chrudinova, M.,Brezinova, J.,Harant, K.,Voldrich, J.,Hajek, M.,Huffman, D.M.,Jiracek, J. An engineered insulin analog with dual insulin and IGF-1 receptor agonism and distinct signaling. Sci Adv, 12:eaeb7558-eaeb7558, 2026 Cited by PubMed Abstract: Insulin and insulin-like growth factors (IGF-1 and IGF-2) regulate metabolism, growth, and development via related receptors. In contexts such as brain function or fetal development, coordinated signaling by all three hormones is essential. We report the engineering of [GluB10, D-HisB24, GlyB31, TyrB32]-insulin (), an analog with high affinity for IR-A, IR-B, and especially IGF-1R. binds IGF-1R ~1000-fold more strongly than native insulin, approaching IGF-1 levels. Cryo-electron microscopy structures reveal how minimal substitutions in enable effective binding to both IR-A and IGF-1R. In neuronal cells, robustly activates both IR and IGF-1R pathways, promotes survival, and exceeds native ligands in neuroprotective assays. In vivo, regulates glucose effectively in mice and rats. Phosphoproteomic profiling confirms dual pathway activation and identifies targets specific to . These findings demonstrate that rational design of dual-receptor agonists can yield potent, versatile ligands with therapeutic promise in metabolic control, neuroprotection, and regeneration. PubMed: 42139356DOI: 10.1126/sciadv.aeb7558 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.4 Å) |
Structure validation
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