Small molecules offer powerful ways to alter protein function. However, most proteins in the human proteome lack small-molecule probes, including the large class of non-catalytic transmembrane receptors, such as death receptors. We hypothesized that small molecules targeting the interfaces between transmembrane domains (TMDs) in receptor complexes may induce conformational changes that alter receptor function. Applying this concept in a screening assay, we identified a compound targeting the TMD of death receptor p75NTRthat induced profound conformational changes and receptor activity. The compound triggered apoptotic cell death dependent on p75NTRand JNK activity in neurons and melanoma cells, and inhibited tumor growth in a melanoma mouse model. Due to their small size and crucial role in receptor activation, TMDs represent attractive targets for small-molecule manipulation of receptor function.

中文翻译：

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靶向死亡受体p75NTR跨膜结构域的小分子诱导黑素瘤细胞死亡并降低肿瘤的生长

小分子提供了改变蛋白质功能的强大方法。但是，人类蛋白质组中的大多数蛋白质缺少小分子探针，包括一大类非催化跨膜受体，例如死亡受体。我们假设靶向受体复合物中跨膜结构域（TMD）之间的界面的小分子可能会诱导改变受体功能的构象变化。将这一概念应用到筛选测定中，我们确定了一种靶向死亡受体p75NTR TMD的化合物，该化合物可诱导深刻的构象变化和受体活性。该化合物触发神经细胞和黑色素瘤细胞中依赖于p75NTR和JNK活性的凋亡细胞死亡，并在黑色素瘤小鼠模型中抑制肿瘤生长。由于其体积小且在受体激活中起着关键作用，