7E72
Crystal structure of Tie2-agonistic antibody in complex with human Tie2 Fn2-3
Summary for 7E72
| Entry DOI | 10.2210/pdb7e72/pdb |
| Descriptor | the chimeric Fab fragment of 3H7 (heavy chain), the chimeric Fab fragment of 3H7 (light chain), Angiopoietin-1 receptor, ... (5 entities in total) |
| Functional Keywords | antigen-antibody complex, agonistic antibody, angiogenesis, vascular stabilization, receptor tyrosine kinase, tie2, membrane protein |
| Biological source | Homo sapiens More |
| Total number of polymer chains | 6 |
| Total formula weight | 142430.71 |
| Authors | Kim, H.M.,Jo, G.H.,Hong, H.J.,Han, A. (deposition date: 2021-02-25, release date: 2021-11-10, Last modification date: 2024-10-30) |
| Primary citation | Jo, G.,Bae, J.,Hong, H.J.,Han, A.R.,Kim, D.K.,Hong, S.P.,Kim, J.A.,Lee, S.,Koh, G.Y.,Kim, H.M. Structural insights into the clustering and activation of Tie2 receptor mediated by Tie2 agonistic antibody. Nat Commun, 12:6287-6287, 2021 Cited by PubMed Abstract: Angiopoietin (Angpt)-Tie receptor 2 (Tie2) plays key roles in vascular development and homeostasis as well as pathological vascular remodeling. Therefore, Tie2-agonistic antibody and engineered Angpt1 variants have been developed as potential therapeutics for ischemic and inflammatory vascular diseases. However, their underlying mechanisms for Tie2 clustering and activation remain elusive and the poor manufacturability and stability of Angpt1 variants limit their clinical application. Here, we develop a human Tie2-agonistic antibody (hTAAB), which targets the membrane proximal fibronectin type III domain of Tie2 distinct from the Angpt-binding site. Our Tie2/hTAAB complex structures reveal that hTAAB tethers the preformed Tie2 homodimers into polygonal assemblies through specific binding to Tie2 Fn3 domain. Notably, the polygonal Tie2 clustering induced by hTAAB is critical for Tie2 activation and are resistant to antagonism by Angpt2. Our results provide insight into the molecular mechanism of Tie2 clustering and activation mediated by hTAAB, and the structure-based humanization of hTAAB creates a potential clinical application. PubMed: 34725372DOI: 10.1038/s41467-021-26620-1 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.094 Å) |
Structure validation
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