8VQE
Homodimeric structure of HER2 S310F extracellular region
Summary for 8VQE
| Entry DOI | 10.2210/pdb8vqe/pdb |
| Related | 8VQD |
| EMDB information | 43439 43440 |
| Descriptor | Receptor tyrosine-protein kinase erbB-2/hIgG1 Fc domain fusion, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose (2 entities in total) |
| Functional Keywords | receptor tyrosine kinase, her2, oncogenic mutation, signaling protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 199404.08 |
| Authors | |
| Primary citation | Bang, I.,Hattori, T.,Leloup, N.,Corrado, A.,Nyamaa, A.,Koide, A.,Geles, K.,Buck, E.,Koide, S. Selective targeting of oncogenic hotspot mutations of the HER2 extracellular domain. Nat.Chem.Biol., 21:706-715, 2025 Cited by PubMed Abstract: Oncogenic mutations in the extracellular domain (ECD) of cell-surface receptors could serve as tumor-specific antigens that are accessible to antibody therapeutics. Such mutations have been identified in receptor tyrosine kinases including HER2. However, it is challenging to selectively target a point mutant, while sparing the wild-type protein. Here we developed antibodies selective to HER2 S310F and S310Y, the two most common oncogenic mutations in the HER2 ECD, via combinatorial library screening and structure-guided design. Cryogenic-electron microscopy structures of the HER2 S310F homodimer and an antibody bound to HER2 S310F revealed that these antibodies recognize the mutations in a manner that mimics the dimerization arm of HER2 and thus inhibit HER2 dimerization. These antibodies as T cell engagers selectively killed a HER2 S310F-driven cancer cell line in vitro, and in vivo as a xenograft. These results validate HER2 ECD mutations as actionable therapeutic targets and offer promising candidates toward clinical development. PubMed: 39438724DOI: 10.1038/s41589-024-01751-w PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.67 Å) |
Structure validation
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