9LFL
Cryo-EM structure of linker-extended biparatopic antibody BA1-GP4 in complex with TNFR2
This is a non-PDB format compatible entry.
Summary for 9LFL
| Entry DOI | 10.2210/pdb9lfl/pdb |
| EMDB information | 63050 |
| Descriptor | Tumor necrosis factor receptor superfamily member 1B, TR92 heavy chain, TR92 light chain, ... (5 entities in total) |
| Functional Keywords | antibody, biparatopic antibody, antagonist, immune system |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 5 |
| Total formula weight | 109917.45 |
| Authors | Otsuki, T.,Matsumoto, S.,Fujita, J.,Miyata, T.,Namba, K.,Kanada, R.,Okuno, Y.,Kamada, H.,Ohno, H.,Akiba, H. (deposition date: 2025-01-08, release date: 2025-08-13, Last modification date: 2025-09-17) |
| Primary citation | Otsuki, T.,Matsumoto, S.,Fujita, J.,Miyata, T.,Namba, K.,Kanada, R.,Okuno, Y.,Kamada, H.,Ohno, H.,Akiba, H. Conversion of an agonistic anti-TNFR2 biparatopic antibody into an antagonist by insertion of peptide linkers into the hinge region. J.Biol.Chem., 301:110548-110548, 2025 Cited by PubMed Abstract: Biparatopic antibodies (BpAbs) bind two different antigen epitopes to form characteristic immunocomplexes. Many BpAbs have been developed for enhanced cross-linking to induce signal transduction or cell internalization, whereas few were reported with smaller immunocomplexes to suppress unwanted signaling. Here, we developed a strategy to induce 1:1 immunocomplex formation to maximize antagonistic function. Various peptide linkers were introduced into the hinge regions of IgG-like agonist BpAbs against tumor necrosis factor receptor 2. Loss of crosslinking activity was observed for one BpAb, allowing the conversion of its function from an agonist to an antagonist. However, cross-linking activity was retained for another agonist BpAb, which binds to a different epitope pair. In a combined analysis of cryo-electron microscopy and coarse-grained molecular dynamics simulations, effect of epitope combination on the stability of 1:1 complexes was observed. These results lead to an understanding of the mechanism and design of BpAbs to adopt a 1:1-binding mode. PubMed: 40752574DOI: 10.1016/j.jbc.2025.110548 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.73 Å) |
Structure validation
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