9X0J
IL-33 and Etokimab fab and Tozorakimab fab ternary complex structure
Summary for 9X0J
| Entry DOI | 10.2210/pdb9x0j/pdb |
| EMDB information | 66435 |
| Descriptor | Interleukin-33 (109-270), Tozorakimab-L Chain, Tozorakimab-H Chain, ... (5 entities in total) |
| Functional Keywords | il33, antibody etokimab fab, antibody tozorakimab fab, cytokine/immune system, cytokine-immune system complex |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 5 |
| Total formula weight | 111969.19 |
| Authors | |
| Primary citation | Chen, J.,Wang, Y.,Wang, X. Structures of clinical antibodies bound to IL-33 uncover two distinct epitopes underlying differential efficacy. Mabs, 18:2639673-2639673, 2026 Cited by PubMed Abstract: Interleukin-33 (IL-33), an alarmin cytokine of the IL-1 family, drives type 2 inflammation through signaling via the ST2 and IL-1RAcP receptors, making it a critical therapeutic target for inflammatory diseases such as asthma and chronic obstructive pulmonary disease. Current therapeutic strategies have primarily focused on antibodies that target IL-33 or ST2 to disrupt their specific interaction. However, the structural mechanisms underlying antibody-mediated neutralization of IL-33 remain poorly understood. Here, we report the structures of three antibodies in clinical trial - etokimab, itepekimab, and tozorakimab - complexed with IL-33, determined by X-ray crystallography and cryo-electron microscopy. Structural analysis reveals two distinct neutralizing epitopes on IL-33, termed Epitope 1 at IL-33/ST2 binding Site 1 and Epitope 2 at IL-33/ST2 binding Site 2. Tozorakimab, which targets Epitope 1, completely blocks ST2 engagement by sterically occluding the ST2 D1-D2 domain-binding interface. In contrast, etokimab and itepekimab, which recognize Epitope 2, interfere with IL-33 recognition of the ST2 D3 domain and thereby only partially inhibit ST2 binding. These structural and biochemical findings provide a molecular explanation for the differential efficacy of the three antibodies in inhibiting IL-33 signaling in cellular assays. Collectively, our results provide valuable insights into the molecular determinants of efficacy for existing IL-33 therapeutics and offer a structural framework for the rational design of next-generation IL-33 targeted inhibitors. PubMed: 41765683DOI: 10.1080/19420862.2026.2639673 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.57 Å) |
Structure validation
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