Molecular Glue that Spatiotemporally Turns on Protein–Protein Interactions,Journal of the American Chemical Society

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Molecular Glue that Spatiotemporally Turns on Protein–Protein Interactions
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2019-04-18 , DOI: 10.1021/jacs.9b02427
Rina Mogaki ₁ , Kou Okuro ₁ , Ryosuke Ueki ₁ , Shinsuke Sando ₁ , Takuzo Aida _{1,

2}

Affiliation

We developed a dendritic molecular glue PCGlue-NBD that can serve universally to "turn on" protein-protein interactions (PPIs) spatiotemporally. PCGlue-NBD carrying multiple guanidinium ion (Gu+) pendants can adhere strongly to target proteins and cover their surfaces including the PPI interface regions, thereby suppressing PPIs with their receptor proteins. Upon irradiation with UV light, PCGlue-NBD on a target protein is photocleaved at butyrate-substituted nitroveratryloxycarbonyl linkages in the dendrimer framework, so that the multivalency for the adhesion is reduced. Consequently, the guest protein is liberated and becomes eligible for a PPI. We found that hepatocyte growth factor HGF, when mixed with PCGlue-NBD, lost the affinity toward its receptor c-Met. However, upon exposure of the PCGlue-NBD/HGF hybrid to light-emitting diode light (365 nm), the PCGlue-NBD molecules on HGF were photocleaved as described above, so that HGF was liberated and retrieved its intrinsic PPI affinity toward c-Met. The turn-on PPI, thus achieved for HGF and c-Met, leads to cell migration, which can be made spatiotemporally with a millimeter-scale resolution by pointwise irradiation with UV light.

中文翻译：

时空开启蛋白质-蛋白质相互作用的分子胶

我们开发了一种树突状分子胶 PCGlue-NBD，它可以普遍用于在时空上“开启”蛋白质-蛋白质相互作用 (PPI)。携带多个胍离子 (Gu+) 悬垂物的 PCGlue-NBD 可以牢固地粘附在目标蛋白上并覆盖其表面，包括 PPI 界面区域，从而通过其受体蛋白抑制 PPI。在紫外线照射下，靶蛋白上的 PCGlue-NBD 在树枝状聚合物框架中的丁酸取代的硝基过氧羰基键上发生光裂解，从而降低了多价粘附。因此，客体蛋白质被释放并成为 PPI 的合格对象。我们发现肝细胞生长因子 HGF 与 PCGlue-NBD 混合时，失去了对其受体 c-Met 的亲和力。然而，在 PCGlue-NBD/HGF 混合物暴露于发光二极管光 (365 nm) 后，HGF 上的 PCGlue-NBD 分子如上所述被光裂解，从而释放 HGF 并恢复其对 c-Met 的固有 PPI 亲和力。由此实现的 HGF 和 c-Met 的开启 PPI 导致细胞迁移，这可以通过紫外光逐点照射以毫米级分辨率在时空上进行。

更新日期：2019-04-18

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