Lo Chih Hung
Department of Biology, Syracuse University, NY 13244, USA.
Interdisciplinary Neuroscience Program, Syracuse University, NY 13244, USA.
Comput Struct Biotechnol J. 2025 Mar 28;27:1335-1341. doi: 10.1016/j.csbj.2025.03.046. eCollection 2025.
Tumor necrosis factor (TNF) receptor 1 (TNFR1) plays a central role in signal transduction mediating inflammation and cell death associated with autoimmune and neurodegenerative disorders. Inhibition of TNFR1 signaling is a highly sought-after strategy to target these diseases. TNFR1 forms pre-ligand dimers held together by the pre-ligand assembly domain (PLAD), which is essential for receptor signaling. TNFR1 dimers form the crucial points of interaction for the entire receptor signaling complex by connecting TNF ligand bound trimeric receptors. While previous studies have shown the feasibility of disrupting TNFR1 dimeric interactions through competitive mechanism that targets the PLAD, our recent studies have demonstrated that small molecules could also bind PLAD to modulate TNFR1 signaling through an allosteric mechanism. Importantly, these allosteric modulators alter receptor dynamics and propagate long-range conformational perturbation that involves reshuffling of the receptors in the cytosolic domains without disrupting receptor-receptor or receptor-ligand interactions. In this study, we perform molecular docking of previously reported allosteric modulators on the extracellular domain of TNFR1 to understand their binding sites and interacting residues. We identify the inter-monomeric space between TNFR1 pre-ligand dimers as a novel binding pocket for allosteric modulators. We further conduct pharmacological analyses to understand the bioactivity of these compounds and their interacting residues and pharmacological properties. We then provide insights into the structure-activity relationship of these allosteric modulators and the feasibility of targeting TNFR1 conformational dynamics. This paves the way for developing new therapeutic strategies and designing chemical scaffolds to target TNFR1 signaling.
肿瘤坏死因子（TNF）受体1（TNFR1）在介导与自身免疫性疾病和神经退行性疾病相关的炎症和细胞死亡的信号转导中起核心作用。抑制TNFR1信号传导是针对这些疾病的一种备受追捧的策略。TNFR1通过配体前组装结构域（PLAD）形成配体前二聚体，该结构域对于受体信号传导至关重要。TNFR1二聚体通过连接TNF配体结合的三聚体受体，形成整个受体信号复合物相互作用的关键点。虽然先前的研究表明通过靶向PLAD的竞争机制破坏TNFR1二聚体相互作用的可行性，但我们最近的研究表明，小分子也可以结合PLAD，通过变构机制调节TNFR1信号传导。重要的是，这些变构调节剂改变受体动力学并传播涉及胞质结构域中受体重新排列的远程构象扰动，而不会破坏受体 - 受体或受体 - 配体相互作用。在本研究中，我们对先前报道的变构调节剂在TNFR1的细胞外结构域上进行分子对接，以了解它们的结合位点和相互作用残基。我们将TNFR1配体前二聚体之间的单体间空间确定为变构调节剂的新型结合口袋。我们进一步进行药理学分析，以了解这些化合物的生物活性、它们的相互作用残基和药理学性质。然后，我们深入了解这些变构调节剂的构效关系以及靶向TNFR1构象动力学的可行性。这为开发新的治疗策略和设计靶向TNFR1信号传导的化学支架铺平了道路。
