| Autor: |
Yan Li, Shuguang Tan, Chang Zhang, Yan Chai, Mengnan He, Catherine W.-H. Zhang, Qihui Wang, Zhou Tong, Kefang Liu, Yifan Lei, William J. Liu, Yingxia Liu, Zhigang Tian, Xuetao Cao, Jinghua Yan, Jianxun Qi, Po Tien, Shan Gao, George F. Gao |
| Jazyk: |
angličtina |
| Rok vydání: |
2018 |
| Předmět: |
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| Zdroj: |
Cell Reports, Vol 25, Iss 4, Pp 909-920.e4 (2018) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2018.09.073 |
| Popis: |
Summary: Monoclonal antibodies (mAbs) targeting the co-stimulatory molecule 4-1BB are of interest for tumor immunotherapy. We determined the complex structures of human 4-1BB with 4-1BB ligand (4-1BBL) or utomilumab to elucidate the structural basis of 4-1BB activation. The 4-1BB/4-1BBL complex displays a typical TNF/TNFR family binding mode. The structure of utomilumab/4-1BB complex shows that utomilumab binds to dimeric 4-1BB with a distinct but partially overlapping binding area with 4-1BBL. Competitive binding analysis demonstrates that utomilumab blocks the 4-1BB/4-1BBL interaction, indicating the interruption of ligand-mediated signaling. The binding profiles of 4-1BBL and utomilumab to monomeric or dimeric 4-1BB indicate limited cross-linking of 4-1BB molecules. These findings provide mechanistic insight into the binding of 4-1BB with its ligand and its agonist mAb, which may facilitate the future development of anti-4-1BB biologics for tumor immunotherapy. : Li et al. report the complex structures of 4-1BB with its ligand 4-1BBL or utomilumab, an agonist monoclonal antibody under clinical investigation. The authors elucidate the binding modes of different forms of 4-1BB to ligand or utomilumab. Keywords: 4-1BB, 4-1BB ligand, 4-1BBL, complex structure, agonist antibody, cross-linking, utomilumab |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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