Solution of the Structure of the TNF-TNFR2 Complex
Solution of the Structure of the TNF-TNFR2 Complex
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DOI：
10.1126/scisignal.2000954
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发表时间：
2010-11-16
影响因子：
7.3
通讯作者：
Tsutsumi, Yasuo
中科院分区：
文献类型：
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作者：
Mukai, Yohei;Nakamura, Teruya;Tsutsumi, Yasuo
肿瘤坏死因子 (TNF) 是一种炎症细胞因子，在各种免疫反应中发挥重要作用，这些免疫反应通过其两种受体 TNF 受体 1 (TNFR1) 和 TNFR2 介导。基于 TNF 的抗体疗法在临床上用于治疗多种慢性自身免疫性疾病；然而，这种治疗有时会导致严重的副作用，这被认为是由两种 TNFR 信号的阻断引起的。因此，了解每种受体识别 TNF 的结构基础对于设计 TNFR 选择性药物至关重要。在这里，我们解析了 TNF-TNFR2 复合物的 3.0 埃分辨率结构，这为 TNFR2 对 TNF 的分子识别提供了深入的了解。与已知的 TNFR1 结构的比较突显了两种受体的配体结合界面之间的一些差异。此外，我们还证明 TNF-TNFR2 在细胞表面形成聚集体，这可能是信号启动所必需的。这些结果可能有助于自身免疫性疾病疗法的设计。
Tumor necrosis factor (TNF) is an inflammatory cytokine that has important roles in various immune responses, which are mediated through its two receptors, TNF receptor 1 (TNFR1) and TNFR2. Antibody-based therapy against TNF is used clinically to treat several chronic autoimmune diseases; however, such treatment sometimes results in serious side effects, which are thought to be caused by the blocking of signals from both TNFRs. Therefore, knowledge of the structural basis for the recognition of TNF by each receptor would be invaluable in designing TNFR-selective drugs. Here, we solved the 3.0 angstrom resolution structure of the TNF-TNFR2 complex, which provided insight into the molecular recognition of TNF by TNFR2. Comparison to the known TNFR1 structure highlighted several differences between the ligand-binding interfaces of the two receptors. Additionally, we also demonstrated that TNF-TNFR2 formed aggregates on the surface of cells, which may be required for signal initiation. These results may contribute to the design of therapeutics for autoimmune diseases.