Tumor necrosis factor receptor 1 (TNFR1) is a transmembrane receptor that plays a key role in the regulation of the inflammatory pathway. While inhibition of TNFR1 has been the focus of many studies for the treatment of autoimmune diseases such as rheumatoid arthritis, activation of the receptor is important for the treatment of immunodeficiency diseases such as HIV and neurodegenerative diseases such as Alzheimer's disease where a boost in immune signaling is required. In addition, activation of other TNF receptors such as death receptor 5 or FAS receptor is important for cancer therapy. Here, we used a previously established TNFR1 fluorescence resonance energy transfer (FRET) biosensor together with a fluorescence lifetime technology as a high-throughput screening platform to identify a novel small molecule that activates TNFR1 by increasing inter-monomeric spacing in a ligand-independent manner. This shows that the conformational rearrangement of pre-ligand assembled receptor dimers can determine the activity of the receptor. By probing the interaction between the receptor and its downstream signaling molecule (TRADD) our findings support a new model of TNFR1 activation in which varying conformational states of the receptor act as a molecular switch in determining receptor function.

中文翻译：

---

TNFR1的构象状态作为受体功能的分子开关。

肿瘤坏死因子受体1（TNFR1）是跨膜受体，在炎症途径的调节中起关键作用。虽然抑制TNFR1一直是许多治疗自身免疫性疾病（例如类风湿性关节炎）的研究的重点，但受体的激活对于免疫缺陷性疾病（例如HIV）和神经退行性疾病（例如阿尔茨海默氏病）的治疗很重要，在这些疾病中，免疫信号的增强是必须的。此外，其他TNF受体（如死亡受体5或FAS受体）的激活对癌症治疗也很重要。这里，我们使用先前建立的TNFR1荧光共振能量转移（FRET）生物传感器以及荧光寿命技术作为高通量筛选平台，以鉴定通过以配体独立的方式增加单体间的间距来激活TNFR1的新型小分子。这表明配体组装前的受体二聚体的构象重排可以决定受体的活性。通过探查受体与其下游信号分子（TRADD）之间的相互作用，我们的发现支持了TNFR1激活的新模型，其中受体的不同构象状态在确定受体功能中起着分子开关的作用。这表明配体组装前的受体二聚体的构象重排可以决定受体的活性。通过探查受体与其下游信号分子（TRADD）之间的相互作用，我们的发现支持了TNFR1激活的新模型，其中受体的不同构象状态在确定受体功能中起着分子开关的作用。这表明配体组装的受体二聚体的构象重排可以决定受体的活性。通过探查受体与其下游信号分子（TRADD）之间的相互作用，我们的发现支持了TNFR1激活的新模型，其中受体的不同构象状态在确定受体功能中起着分子开关的作用。