Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Nat Chem Biol. 2020 Nov;16(11):1218-1226. doi: 10.1038/s41589-020-0625-7. Epub 2020 Aug 17.
The ubiquitin-proteasome system (UPS) is a highly regulated protein disposal process critical to cell survival. Inhibiting the pathway induces proteotoxic stress and can be an effective cancer treatment. The therapeutic window observed upon proteasomal blockade has motivated multiple UPS-targeting strategies, including preventing ubiquitination altogether. E1 initiates the cascade by transferring ubiquitin to E2 enzymes. A small molecule that engages the E1 ATP-binding site and derivatizes ubiquitin disrupts enzymatic activity and kills cancer cells. However, binding-site mutations cause resistance, motivating alternative approaches to block this promising target. We identified an interaction between the E2 N-terminal alpha-1 helix and a pocket within the E1 ubiquitin-fold domain as a potentially druggable site. Stapled peptides modeled after the E2 alpha-1 helix bound to the E1 groove, induced a consequential conformational change and inhibited E1 ubiquitin thiotransfer, disrupting E2 ubiquitin charging and ubiquitination of cellular proteins. Thus, we provide a blueprint for a distinct E1-targeting strategy to treat cancer.
泛素-蛋白酶体系统（UPS）是一种高度调控的蛋白降解过程，对细胞存活至关重要。抑制该途径会导致蛋白毒性应激，可作为有效的癌症治疗方法。在蛋白酶体阻断时观察到的治疗窗口促使人们采用了多种 UPS 靶向策略，包括完全阻止泛素化。E1 通过将泛素转移到 E2 酶上来启动级联反应。一种与 E1 ATP 结合位点结合并衍生出泛素的小分子会破坏酶的活性并杀死癌细胞。然而，结合位点的突变会导致耐药性，因此需要寻找其他方法来阻断这一有前途的靶点。我们发现 E2 N 端α-1 螺旋与 E1 泛素折叠结构域内的一个口袋之间存在相互作用，这可能是一个可成药的位点。模拟 E2α-1 螺旋的订书肽结合到 E1 凹槽中，诱导了相应的构象变化，并抑制了 E1 泛素硫转移酶的活性，从而破坏了 E2 泛素的加载和细胞蛋白的泛素化。因此，我们为治疗癌症提供了一种独特的 E1 靶向策略的蓝图。
