8Y2K

The crystal structure of QX006N-Fab

8Y2K の概要

• エントリーDOI: 10.2210/pdb8y2k/pdb
• 分子名称: QX006N-Fab-LC, QX006N-Fab-HC (2 entities in total)
• 機能のキーワード: therapeutic monoclonal antibody, qx006n, immune system
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 95436.49

構造登録者

Li, W.,Feng, W. (登録日: 2024-01-26, 公開日: 2024-12-04)

主引用文献

Chen, X.,Ke, H.,Li, W.,Yin, L.,Chen, W.,Chen, T.,Wu, Y.,Qiu, J.,Feng, W.
Structural basis for the recognition of IFNAR1 by the humanized therapeutic monoclonal antibody QX006N for the treatment of systemic lupus erythematosus.
Int.J.Biol.Macromol., 268:131721-131721, 2024

PubMed Abstract: Interferon (IFN) alpha/beta receptor 1 (IFNAR1) is indispensable for antiviral responses and the immune regulation. Dysregulation of the IFNAR1-mediaetd signaling pathways leads to deleterious autoimmune diseases such as systemic lupus erythematosus (SLE). QX006N, a humanized therapeutic monoclonal antibody, specifically targets human IFNAR1 and is in the clinical trial phase for treating SLE, but the molecular mechanism underlying the QX006N-mediated recognition of IFNAR1 remains unclear. Here, we report the high neutralization activities of QX006N against IFNAR1-mediated signal transduction. Meanwhile, we determine the structures of the fragment antigen-binding domain (Fab) of QX006N (QX006N-Fab) and QX006N-Fab in complex with the subdomains 1-3 of IFNAR1 (IFNAR1-SD123) at 2.87 Å and 2.68 Å resolutions, respectively. In the structure of the QX006N-Fab/IFNAR1-SD123 complex, QX006N-Fab only recognizes the SD3 subdomain of IFNAR1 by the hydrophobic, hydrogen-bonding and electrostatic interactions. Compared with the structure of the IFN/IFNAR1/IFNAR2 complex, the binding of QX006N-Fab to IFNAR1-SD3 blocks its association with IFN due to steric hindrance, which inhibits the IFN/IFNAR1/IFNAR2 complex formation for signal transduction. The results of this study provide the structural evidence for the specific targeting of IFNAR1 by the therapeutic antibody QX006N and pave the way for the rational design of antibody drugs to combat IFNAR1-related autoimmune diseases.

PubMed: 38649079
DOI: 10.1016/j.ijbiomac.2024.131721

実験手法

X-RAY DIFFRACTION (2.87 Å)