22GC
The structure of HER2-m66-trastuzumab
Summary for 22GC
| Entry DOI | 10.2210/pdb22gc/pdb |
| EMDB information | 68255 |
| Descriptor | Trastuzumab FAB LIGHT CHAIN, m66 (murine-derived) HEAVY CHAIN,, Receptor tyrosine-protein kinase erbB-2, ... (6 entities in total) |
| Functional Keywords | human epidermal growth factor receptor 2 (her2);m66 (murine-derived);r40 (rabbit-derived), protein binding/immune system, protein binding-immune system complex |
| Biological source | Homo sapiens More |
| Total number of polymer chains | 6 |
| Total formula weight | 177179.97 |
| Authors | |
| Primary citation | Liu, C.,Ren, Y.,Luo, X.,Zhou, P.,Du, X.,Wang, Q.,Han, X.,Xu, Y.,Wang, P.,Zhao, D.,Yang, H. Inhibition of HER2 signaling and breast cancer cell growth with a novel antibody targeting HER2 ECD III/IV. Plos One, 21:e0338127-e0338127, 2026 Cited by PubMed Abstract: Human epidermal growth factor receptor 2 (HER2), a ligand-independent tyrosine kinase receptor belonging to the EGFR family, serves as a key oncogenic driver in breast, gastric, and several other solid tumors. Although anti-HER2 therapies have substantially improved survival outcomes-particularly in breast and gastric cancers-treatment resistance and cancer recurrence remain major clinical challenges. Thus, developing novel antibodies exhibiting complementary effects to the current anti-HER2 therapies could provide additional therapeutic benefits. Here, we describe two novel HER2-targeting monoclonal antibodies, m66 (murine-derived) and r40 (rabbit-derived), which inhibit breast cancer cell proliferation in vitro. Of the two, antibody r40 exhibits stronger suppression of the PI3K/AKT and MAPK signaling pathways compared to m66. Moreover, the addition of r40 to the combination of trastuzumab and pertuzumab leads to a significantly enhanced inhibitory effect. We also determined the cryo-EM structures of the HER2-m66-trastuzumab ternary complex and the HER2-r40-trastuzumab-pertuzumab tetrameric complex, at overall resolutions of 3.2 Å and 3.1 Å, respectively. Structural analyses reveal that m66 recognizes an epitope overlapping with that of pertuzumab, whereas r40 binds within the HER2 ECD III/IV-a region distinct from the binding sites of both trastuzumab and pertuzumab. These findings identify r40 as a promising therapeutic candidate for use in combination with trastuzumab and pertuzumab in the treatment of HER2-positive breast cancer. PubMed: 41538393DOI: 10.1371/journal.pone.0338127 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.2 Å) |
Structure validation
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